Therapeutic options for steroid-refractory acute and chronic GVHD: an evolving landscape

ABSTRACT

Introduction

The traditional therapeutic modalities to manage SR-acute GVHD have focused on the inhibition of the alloreactive T-cell response, while in the setting of SR-chronic GVHD the focus has been on a combination of T-cell and B-cell targeting strategies. However, new therapeutic modalities have shown promise. The purpose of this review is to summarize the current treatment landscape of SR-acute and chronic GVHD.

Areas covered

A systematic search of MEDLINE, EMBASE, and clinicaltrials.gov databases for published articles, abstracts, and clinical trials pertaining to available therapeutic modalities for SR-acute and SR-chronic GVHD was conducted. Also highlighted is a number of ongoing clinical trials in both SR-acute and SR-chronic GVHD with strategies targeting the JAK-1/2 pathway, the Treg:Tcon ratio, the immunomodulation mediated by mesenchymal stem cells, and the gut microbiome, among others. Expert opinion: Ruxolitinib has emerged as the preferred therapeutic modality for SR-acute GVHD, with alpha-1-antitrypsin and extracorporeal photophoresis (ECP) being reasonable alternatives. Ruxolitinib and Ibrutinib are among the preferred options for SR-chronic GVHD, with ECP being a viable alternative particularly if the skin is involved. A number of novel therapeutic modalities, including those enhancing the activity of regulatory T-cells have shown great promise in early phase trials of SR-chronic GVHD.

KEYWORDS:

• GVHD
• steroid-refractory
• ruxolitinib
• alpha-1 antitrypsin
• ECP
• ibrutinib
• interleukin-2
• KD-025

Article highlights

• Clinical studies of SR-acute and chronic GVHD are limited by the definition of steroid-refractoriness, relying on a time-frame definition that does not necessarily correlate with disease biology.

• Ruxolitinib has emerged as the preferred therapeutic modality for SR-acute GVHD, having received FDA approval for this indication. It is also among the preferred options for SR-chronic GVHD.

• Other therapies for SR-acute GVHD based on available evidence include alpha-1 antitrypsin and extracorporeal photopheresis (ECP). The use of infliximab, etanercept, and vedolizumab in gut SR-acute GVHD and basiliximab in skin and gut SR-acute GVHD may be considered as additional options in select cases, but requires further validation in prospective studies.

• Ibrutinib has received FDA approval for SR-chronic GVHD based on a phase Ib/II study, but suffers from a high rate of discontinuation. A phase III RCT of Ibrutinib in SR-chronic GVHD is required.

• ECP remains a viable option for SR-chronic GVHD, particularly if it affects the skin.

• Novel therapeutic modalities currently being explored in SR-chronic GVHD include those that target IL-2 signaling (aldesleukin, AMG 592), those targeting T-cell costimulation via CTLA4 (Abatacept) and those increasing the proportion of T-regulatory cells (Tregs) with respect to other effector T-cell populations (the Rho kinase KD-025).

This box summarizes key points contained in the article.

Declaration of interest

J Antin is on the DSMB for CSL Behring. 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.