Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease

Abstract

Introduction Graft-versus-host disease (GVHD) continues to be the major lethal complication of allogeneic hematopoietic stem cell transplantation (HCT) but the standard of care, high dose steroids, has not changed in 40 years. Approximately 50% of GVHD patients will develop steroid refractory disease, typically involving the gastrointestinal (GI) tract, which has a very poor prognosis. Newly developed GVHD biomarker-based risk scores provide the first opportunity to treat patients at the onset of symptoms according to risk of steroid failure. Furthermore, improvements in our understanding of the pathobiology of GVHD, its different signaling pathways, involved cytokines, and the role of post-translational and epigenetic modifications, has identified new therapeutic targets for clinical trials. Areas covered This manuscript summarizes the pathophysiology, diagnosis, staging, current and new targeted therapies for GVHD, with an emphasis on GI GVHD. A literature search on PubMed was undertaken and the most relevant references included. Expert Opinion The standard treatment for GVHD, high dose steroids, offers less than optimal outcomes as well as significant toxicities. Better treatments, especially for GI GVHD, are needed to reduce non-relapse mortality after allogeneic HCT. The identification of high risk patients through a biomarker-defined scoring system offers a personalized approach to a disease that still requires significant research attention.

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

“…Unfortunately, non-response to first-line treatment is common, and data regarding the effectiveness of various second-line treatment modalities is limited. Supportive care throughout the duration of illness is of critical importance and focuses on symptomatic management 139 .…”

“…111 There are also data showing that patients with lower gastrointestinal involvement are at particularly high risk of non-response 155 . Unfortunately, there is an insufficient amount of quality data to guide the management of patients who fail to respond to corticosteroids, and their outcomes are generally poor 139 . Several second-line therapies are currently available to treat patients who are steroid-refractory, including lymphocyte-depleting agents, cell cycle inhibitors, antimetabolites, TNF antagonists, inhibitors of leukocyte trafficking, antibodies directed against various interleukins, extra corporeal photopheresis and others 139 .…”

“…Unfortunately, there is an insufficient amount of quality data to guide the management of patients who fail to respond to corticosteroids, and their outcomes are generally poor 139 . Several second-line therapies are currently available to treat patients who are steroid-refractory, including lymphocyte-depleting agents, cell cycle inhibitors, antimetabolites, TNF antagonists, inhibitors of leukocyte trafficking, antibodies directed against various interleukins, extra corporeal photopheresis and others 139 . A detailed discussion of second-line therapies is beyond the scope of this article, and we direct the reader to a relevant review 139 .…”

Therapy response of glucocorticoid-refractory acute GVHD of the lower intestinal tract

“…To describe GI-GVHD outcomes we analyzed data collected over a period of 6 years on patients developing GI-GVHD at MCUF. The motivation was that previous reports on GI-GVHD had analyzed patients in the era before ruxolitinib [ 29 , 30 ] and that novel therapies that target selectively GI-GVHD showed efficacy in mice. These GI-GVHD regenerative approaches include interleukin-22 (IL-22) [ 24 , 25 ], R-spondin [ 26 , 27 ], and GLP-2 [ 28 ].…”

“…To test these approaches in the clinic it will be important to assess selectively the therapy response of lower intestinal tract aGVHD in a real-world setting in the era of ruxolitinib. Previous reports on GI-GVHD therapy response date back to the time before ruxolitinib was used for SR-GVHD [ 29 , 30 ]. To address that, we report here incidence, therapy response and outcome of patients developing lower intestinal tract acute GVHD at the Medical Center of the University of Freiburg (MCUF) over a time period of 6 years.…”