Individualized Dose Study of ATG in Haploidentical Hematopoietic Stem Cell Transplantation
Study Details
Study Description
Brief Summary
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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 Design
Arms and Interventions
| 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 7 mg/kg to10mg/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 7 mg/kg to 13mg/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
|
Outcome Measures
Primary Outcome Measures
- Number of participants with aGVHD as assessed by acute graft versus host disease grading criteria (refer to Glucksberg criteria) [100 days after transplantation]
Defined as the proportion of participants who developed acute GVHD
- The cumulative incidences of CMV reactivation [1 years after transplantation]
The cumulative incidences of CMV reactivation in participants after transplantation, tested by realtime PCR
- The cumulative incidences of EBV reactivation [1 years after transplantation]
The cumulative incidences of EBV reactivation in participants after transplantation, tested by realtime PCR
Secondary Outcome Measures
- Nonrelapse mortality (NRM) [1 years after transplantation]
Defined as the proportion of subjects who died due to causes other than malignancy relapse
- Incidence of viral reactivations [6 months after transplantation]
Viral reactivations refer to participants experienced one or more of the following events: CMV viremia, CMV disease, EBV viremia or posttransplant lymphoproliferative disease.
- Number of participants with cGVHD as assessed by chronic graft versus host disease grading criteria (refer to NIH criteria) [1 years after transplantation]
cGvHD was diagnosed and graded according to the 2014 National Institutes of Health (NIH) consensus criteria: mild, moderate or severe respectively.
- Leukocyte engraftment [1 month after transplantation]
Leukocyte engraftment was defined as the first of three consecutive days of peripheral blood neutrophil count >500/ul
- Platelet engraftment [1 month after transplantation]
Platelet engraftment was defined as the first of seven consecutive days of platelet counts of >20000/ul.
- Overall survival (OS) [365 days after transplantation]
Defined as the time from study enrollment to death due to any cause
- DFS(disease-free survival ) [1 years after transplantation]
DFS was defined as survival with no evidence of relapse or progression.
- GRFS (GVHD free, relapse free survival) [1 years after transplantation]
GVHD-free, relapse-free survival (GRFS) was defined as survival with no evidence of grade III-IV acute GVHD or cGVHD requiring immunosuppressive treatment, and without disease recurrence or death from any cause during the first year after transplantation.
- infection rate [1 years after transplantation]
Defined as the proportion of participants who developed all kinds of infection
Eligibility Criteria
Criteria
Inclusion Criteria:
- Haploidentical hematopoietic stem cell transplant recipients Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that the participants understand the purpose of and procedures required for the study and are willing to participate in the study
Exclusion Criteria:
- Participants with any conditions not suitable for the trial (investigators' decision)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Chinese PLA General Hospital | Beijing | Beijing | China | 100853 |
Sponsors and Collaborators
- Chinese PLA General Hospital
Investigators
- Study Chair: Dai-hong Liu, Dr., Chinese PLA General Hospital
Study Documents (Full-Text)
None provided.More Information
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.
- 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.
- 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.
- Remberger M, Svahn BM, Mattsson J, Ringdén O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation. 2004 Jul 15;78(1):122-7.
- 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.
- S2020-484-01