ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint

Abstract

This article has a companion Point by Bacigalupo.Despite improvements in HLA matching, quality control measures, and supportive care used in hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) remains a common cause of morbidity and mortality in transplant recipients. 1 The primary goal of HSCT is to cure the underlying hematological disorder with as little residual disability as possible. Achieving this goal requires supporting the patient through a conditioning regimen and its associated toxicity, opportunistic infections, and GVHD while avoiding relapse. Despite recognizing that donor T cells are critical in the establishment of both acute and chronic GVHD, it is important to remember that these cells also help in preventing opportunistic infections and providing a graft-versus-leukemia (GVL) effect when necessary. It was not surprising then that early on we discovered that ex vivo T-cell depletion could prevent or minimize GVHD, but at the cost of increases in mortality from rejection, relapse, and opportunistic infection.It is generally accepted that preventing GVHD is more effective than treating it once it has been established. The use of antithymocyte globulin (ATG) reflects a form of in vivo T-cell depletion, which concomitantly depletes host T cells that have survived the conditioning regimen. This reduces the risk of rejection, while similarly depleting newly infused donor T cells, thus potentially reducing GVHD, GVL, and the passive transfer of memory T cells that reconstitute early immunity. An analysis of ATG's value is complicated by considerations of ATG formulation, sensitivity of the underlying disease to GVL, intensity of conditioning regimen, donor source, and other medications used for GVHD prophylaxis. The decision to use ATG must balance the circumstances in which ATG may be beneficial by reducing the incidence of GVHD with the situations in which ATG may be either neutral or harmful by increasing the risk of Epstein-Barr virus (EBV) posttransplant lymphoproliferative disease and other infections as well as relapse. Not all ATG formulations are the sameAlthough randomized controlled trials have demonstrated that ATG can reduce the risk of GVHD, 2,3 the differences in dosage and formulation of ATG make it difficult to generalize these results. For example, rabbit ATG (Thymoglobulin) is associated with more effective depletion of lymphocytes than horse ATG (ATGAM). 4 In addition to lymphocyte depletion, rabbit but not horse ATG enhances the number and function of regulatory T cells, 5,6 which are important in suppressing immune response and maintaining tolerance. The preservation or permissive expansion of regulatory T cells may limit GVHD after HSCT because these cells are needed for tolerance, controlling alloreactive donor lymphocytes involved in GVHD as well as innate and adaptive immune responses. These mechanistic differences between rabbit and horse ATG result in different outcomes in patients receiving immunosuppressive therapy or bone marrow transplantat...

Successful Outcome in Patients with Fanconi Anemia Undergoing T Cell-Replete Mismatched Related Donor Hematopoietic Cell Transplantation Using Reduced-Dose Cyclophosphamide Post-Transplantation

“…All patients received ATG, which could have contributed to the lower incidence of severe GVHD. The use of ATG reflects a form of in vivo T cell depletion, which concomitantly depletes host T cells that survive the conditioning regimen and reduces the risk of rejection while depleting newly infused donor T cells, thereby potentially reducing GVHD [41]. In this study, we used the same low-dose PT-CY regimen for GVHD prophylaxis as has been reported for patients with FA, but we continued immunosuppressive therapy with cyclosporine and MMF for 6 months and then tapered it gradually in those without active GVHD.…”

Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation

“…The most common ATG formulations include Thymoglobulin (Genzyme-Sanofi, Cambridge, MA) and ATLG Grafalon (ATLG; previously referred to as ATG Fresenius; Neovii Pharmaceuticals AG, Rapperswil, Switzerland), which are generated by immunizing rabbits with human thymocytes or Jurkat T lymphoblastoid cells, respectively. The relative efficacies of these formulations have not been compared head-to-head in vivo, and current recommended HCT dosages for these formulations differ by nearly 10-fold despite in vitro evidence of similar T cell cytotoxicity [5,6].…”

Impact of antithymocyte globulin on outcomes of allogeneic hematopoietic cell transplantation with TBI

“…37 Another potential variable is the difference in ATG formulations (thymoglobin versus Grafalon) used across the studies. 40,41 It is unknown whether in vivo TCD is comparable between these 2 formulations because of the absence of dose equivalence and head-to-head comparisons between thymoglobin and Grafalon. In a meta-analysis of prospective studies, Gagelmann et al showed that Grafalon was associated with improved GVHD (acute and chronic) rates compared with thymoglobin.…”