New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity

Abstract

In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin(®) was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn's disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.

Fig. 1

rATG (Thymoglobulin^®) dose in clinical studies according to year of publication with (a) standard triple maintenance regimen [, , –34]; (b) steroid-sparing regimen [–46] and (c) CNI-sparing regimen [, , –56]. Doses shown are protocol specified or, if unavailable, mean dose administered. CNI calcineurin inhibitor, rATG rabbit antithymocyte globulin

Fig. 2

Chronic GvHD in patients with hematological malignancy undergoing unrelated HSCT randomized to rATG or no rATG [221]. GvHD graft-versus-host disease, HSCT hematopoietic stem cell transplantation, rATG rabbit antithymocyte globulin

Fig. 3

Five-year outcomes from a randomized trial of patients with hematologic malignancies receiving reduced-intensity conditioning with fludarabine and either rATG (2.5 mg/kg) with busulfan (n = 69) or total body irradiation (n = 70) prior to HSCT from an HLA-identical sibling [236]. HLA human leukocyte antigen, HSCT hematopoietic stem cell transplantation, rATG rabbit antithymocyte globulin