New therapeutic targets and biomarkers for acute graft-versus-host disease (GVHD)

ABSTRACT

Introduction

Acute Graft-versus-Host Disease (GVHD) is the major toxicity of allogeneic hematopoietic cell transplantation (HCT). Systemic steroids are the standard primary treatment but only half of the patients will respond completely and the survival of steroid-refractory patients is poor. The gastrointestinal (GI) tract is a key target organ that usually determines a patient’s response to therapy.

Areas covered

This review summarizes the use of clinical grading systems and biomarkers in GVHD treatment and highlights pathophysiologic phases of acute GVHD as context for the mechanisms of action and therapeutic targets of various approaches. We reviewed >100 publications and performed a search of ongoing, current clinical trials on the emerging therapeutic targets for prophylaxis and treatment of acute GVHD. Search databases included clinicaltrials.gov and PUBMED. Search terms and keywords included ‘acute graft-versus-host disease,’ ‘GVHD,’ ‘graft versus host,’ ‘treatment.’

Expert opinion

Future strategies will employ a risk-adapted therapy using biomarkers, which more accurately predict 6-month NRM. Strategies for high-risk patients will inhibit GI tract damage by selective targeting of effectors (e.g. inhibition of JAK signaling in T cells), blockade of trafficking through mAbs against integrin receptors, or enhancement of target cell survival. Future strategieswill reduce immunosuppression to avoid risk of infections and relapse.

KEYWORDS:

• Allogeneic hematopoietic cell transplantation
• clinical trials
• immunosuppression
• serum biomarkers
• steroid refractory acute GVHD
• acute GVHD
• graft versus host disease (GVHD)

Declaration of interest

JLM Ferrara has a patent on biomarkers for acute GVHD and consultancies for the following companies: Xenikos, Equillium, Mallinckrodt; research support from Incyte, Kamada.

The author(s) 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.

Article Highlights

• Acute Graft-versus-Host Disease (GVHD) is the major toxicity of allogeneic hematopoietic cell transplantation (HCT).

• Systemic steroids are the standard primary treatment and steroid refractory acute GVHD portends poor survival post-HCT

• Gastrointestinal tract crypts are key cellular targets of acute GVHD and strategies that prevent their damage are attractive

• The MAGIC Algorithm Probability (MAP) combines two biomarkers that estimate the extent of GI crypt damage. Future treatments are likely to use risk adapted strategies guided on biomarkers.