Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel

Francesca Bonifazi,Alessandro Rambaldi,Gérard Socie,Irwin Walker,Jaap Jan Boelens,Jürgen Finke,Carlos Solano,Mohamad Mohty,Arnon Nagler,Hildegard Greinix,Nicolaus Kröger,Jakob Passweg,Andrea Bacigalupo,Marie-Thérèse Rubio,Giovanni Barosi

doi:10.1038/s41409-020-0792-x

Abstract

This collaborative initiative aimed to provide recommendations on the use of polyclonal antithymocyte globulin (ATG) or anti-T lymphocyte globulin (ATLG) for the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). A comprehensive review of articles released up to October, 2018 was performed as a source of scientific evidence. Fourteen clinically relevant key questions to the domains indication, administration, and post-transplant management were developed and recommendations were produced using the Delphi technique involving a Panel of 14 experts. ATG/ATLG was strongly recommended as part of myeloablative conditioning regimen prior to matched or mismatched unrelated bone marrow or peripheral blood allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD. ATG/ATLG was also recommended prior to HLA-identical sibling peripheral HSCT with good but lesser bulk of evidence. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG was deemed appropriate to reduce the incidence of acute and chronic GvHD, but a higher risk of relapse should be taken into account. Recommendations regarding dose, application, and premedication were also provided as well as post-transplant infectious prophylaxis and vaccination. Overall, these recommendations can be used for a proper and safe application of polyclonal ATG/ATLG to prevent GvHD after allogeneic HSCT.

Highlights

Graft-versus-host disease (GvHD) is one of the most important factor limiting the success of allogeneic hematopoietic stem cell transplantation (HSCT) [1, 2] because it negatively affects both the duration and quality of life of patients after transplant [3].The most widely used strategy for GVHD prevention, at least in Europe [4], is the addition of rabbit antilymphocyte serum to the standard prophylaxis with a calcineurin inhibitor and either methotrexate or mycophenolate mofetil
antithymocyte globulin (ATG)/anti-Tlymphocyte globulin (ATLG) is recommended as part of chemotherapy- or total body irradiation (TBI)-based myeloablative conditioning (MAC) regimen prior to matched or mismatched unrelated bone marrow (BM) or peripheral blood (PB) allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD
The Panel agreed that ATG/ATLG should be recommended prior to HLA-identical sibling PB allogeneic HSCT, even though the evidence of efficacy is based only on one randomized trial, compared with four trials in unrelated allogeneic HSCT

Summary

Introduction

The most widely used strategy for GVHD prevention, at least in Europe [4], is the addition of rabbit antilymphocyte serum to the standard prophylaxis with a calcineurin inhibitor and either methotrexate or mycophenolate mofetil. There are several formulations of polyclonal antilymphocyte sera available in different countries, generated in animals (rabbits, horses, and pigs) by inoculation of human thymocytes or human cell line. Available rabbit polyclonal antilymphocyte sera are the antithymocyte globulin (ATG) (Sanofi Genzyme, Cambridge MA), derived from rabbit vaccination with human thymocytes, and the anti-Tlymphocyte globulin (ATLG) (Neovii, Rapperswil, Switzerland, formerly ATG Fresenius®), derived from the human Jurkat T-cell line. Horse ATG (hATG, ATGAM®, Pfizer Inc NY, US) is used as first-line therapy of moderate–severe aplastic anemia [5] as well as GvHD prophylaxis [6]. We restrict the consensus to rabbit sera because of their prevalent use as drugs for GvHD prevention

Results

Discussion

Conclusion