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.

KEYWORDS:

• Biomarkers
• GVHD
• graft-versus-host disease
• microbiome
• Paneth cells
• steroid-refractory GVHD
• treatment

Article highlights

• Acute GVHD develops in 40–60% of allogeneic HCT recipients and is the major cause of NRM. The standard first-line therapy for acute GVHD is high-dose steroids, but 50% of cases are steroid refractory. GI GVHD accounts for the majority of NRM because of its high rate of treatment failure.

• New treatments for GVHD under study that exploit new targets involved in GVHD pathophysiology include blockade of leukocyte trafficking, JAK inhibition, histone deacetylase inhibitors, alpha-1 antitrypsin, induction of regulatory T cells, and restoration of GI barrier function through cytokines.

• A validated scoring system based on GVHD biomarkers (Ann Arbor risk scores) objectively stratifies patients according to risk of primary treatment failure and can identify patients for clinical trials before steroid refractory GVHD has developed.

• The loss of diversity in the GI microbiota is associated with increased GVHD mortality and relates to different factors, including exposure to antibiotics. Preservation or restoration of a healthy GI microbiome is an alternative strategy to treat GI GVHD.

This box summarizes key points contained in the article.

Declaration of interest

J Ferrara and J Levine both own a patent on GVHD biomarkers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.