Pharmaceutical and Cellular Strategies in Prophylaxis and Treatment of Graft-Versus-Host Disease

D.      Wolff; B.      Steiner; G.      Hildebrandt; M.      Edinger; E.      Holler

Abstract

Acute and chronic GVHD after allogeneic hematopoetic stem cell transplantation are still associated with significant morbidity and mortality. For prophylaxis of acute GVHD calcineurin inhibitors in combination with an antimetabolite (MTX or MMF) are administered, and these therapies are based on controlled studies. New prophylaxis strategies include mTOR-inhibitors in combination with tacrolimus but require confirmation by controlled trials. First-line treatment of acute GVHD consists mainly of steroids with doses ranging from 1 mg/kg/day prednisone to 3 mg/kg/day methylprednisolone. Second-line treatment of acute GVHD after failure of steroids is less well defined due to the lack of controlled studies. Treatment options are the use of cytotoxic antibodies (ATG, campath), cytokine blocking agents (etanercept, daclizumab), immunomodulating modalities (photopheresis), and antimetabolites (pentostatin, MMF). Recently, cellular approaches were developed, such as the adoptive transfer of mesenchymal stem cells. Nevertheless steroid-resistant acute GVHD is still a main challenge in alloHSCT and associated with high mortality. First-line treatment of chronic GVHD is also based on steroids with 1 mg/kg/day prednisolone or prednisone, which are often combined with calcineurin inhibitors. There is no consensus on second-line treatment of chronic GVHD and most therapies are solely based on phase II trials. Treatment options are the use of immunomodulating modalities (photopheresis, mTOR-inhibitors) and antimetabolites (MMF, MTX, pentostatin). Recent reports showed an efficacy of rituximab in selected patients. Other treatment options are low dose total nodal irradiation or the use of antibodies like ATG. Moreover, successful topical treatment of manifestations of chronic GVHD manifestations has been reported consisting of topical steroids like budesonide, topical calcineurin inhibitors, or PUVA.

Keywords: Allogeneic hematopoietic stem cell transplantation, GVHD, treatment, prophylaxis, steroids, calcineurin inhibitors, MTX, Sirolimus