Five Future Possibilities for Treating Acute GVHD That Is Refractory to Steroids

Portia Smallbone, M.B.B.S.

The FDA approved Jakafi (ruxolitinib) in 2019 as a treatment for graft-versus-host disease (GVHD) that doesn’t respond to steroids. The addition of the oral Janus kinase 1/2 inhibitor to the GVHD armamentarium has been a major advance, but some patients don’t respond to Jakafi. Moreover, in a review paper published in the American Journal of Hematology, lead and corresponding author Portia Smallbone, M.B.B.S., of the University of Texas MD Anderson Cancer Center, and her MD Anderson colleagues, Rohtesh S. Mehta, M.P.H., M.S., and Amin Alousi, M.D., say the benefits of Jakafi have not translated into improved overall survival. There is, they wrote, “a clear and urgent need for better therapies in patients suffering from SR-AGVHD [steroid-refractory graft-versus-host-disease].” In the latter half of the review, they discuss five experimental “third line” approaches to treating acute GVHD.

Mesenchymal stem cells

Mesenchymal stem cells are stem cells that can be obtained from bone marrow, adipose tissue, or umbilical cord, explain Smallbone and colleagues. They can be infused intravenously and have been shown to have immunological properties that suggest they could be used as treatment of steroid-refractory GVHD. But Smallbone, Mehta and Alousi say the trial data concerning efficacy has been “contentious.” Case reports and European studies showed remarkable results that couldn’t be reproduced. They cite a Cochrane review of 12 randomized studies conducted before 2018 that, they say, found no evidence of efficacy. But they also cite a real-world evidence study of 64 patients that they characterize as having “encouraging” results with respect to overall survival. The inconsistency, they say, could be chalked up to differences in study design, manufacturing differences and variation in how respond is defined.

The FDA approved Ryoncil (remestemcel-L) in December 2024 for steroid-refractory acute GVHD graft in pediatric patients. Smallbone and her colleagues said that approval was “a significant milestone and may pave the way for more robust studies in the adult population.”

Fecal transplants

Rohtesh S. Mehta, M.P.H., M.S.

Fecal microbiota transplantation involves transplanting bacteria found in the fecal matter of healthy individuals into patients with compromised gut microbiomes. Positive results from case reports and small studies have stirred up interest in fecal microbiota transplantation for acute GVHD, which tends to attack the gastrointestinal tract along with the liver and skin. Smallbone and her colleague cite a meta-analysis of 23 studies involving 242 patients that found a pooled clinical remission rate of 64%. They also mention a single-arm European study of 111 patients that found a reported overall gastrointestinal response rate of 53% in patients with higher grades of gastrointestinal GVHD. Their takeaway is that although the early studies of fecal microbiota transplants produced promising results, evidence from larger studies is needed to confirm them.

AAT

A1-antitrypsin (AAT) is a protease inhibitor produced by the liver that damps down proinflammatory cytokines and nudges proinflammatory T-effector cells to become anti-inflammatory regulatory cells, explain Smallbone, Mehta and Alousi. They cite promising results from a single-arm trial and say results from a phase 3, placebo-controlled trial of AAT, sponsored by CSL Behring, are “highly awaited.”

GLP-2 inhibitors

Amin Alousi, M.D.

Glucagon-like peptide 1 (GLP-1) has become well-known because GLP-1 drugs, such as Wegovy (semaglutide) and Zepbound (tirzepatide), are prescribed for weight loss. Glucagon-like peptide (GLP-2) is a related hormone, also produced by intestinal L cells, that has protective and regenerative effects on the gut, explain Smallbone and her colleagues. Gattex (teduglutide) is a GLP-2 analogue that the FDA approved as a treatment for short bowel syndrome in 2012. Smallbone and her colleagues mention a study of Gattex as a treatment of GVHD in young adults and children that was published in 2024 in the journal Transplantation and Cellular Therapy as showing “promising” results. Positive results for a different GLP-2 drug, apraglutide, were presented at the American Society of Hematology meeting in December 2024, although the future of the drug is in doubt after the FDA ordered the drug’s maker, Ironwood Pharmaceuticals, to conduct another phase 3 trial of the drug as a treatment for short bowel syndrome.

RIPK1

Receptor interacting protein kinase (RIPK1) is a regulator of apoptosis in the gut. Smallbone, Mehta and Alousi say that experiments in mice suggest that RIPK1 inhibition may reduce GVHD-induced apoptosis and associated mortality. A prospective trial studying the approach ended prematurely because the sponsor stopped supporting it, but Smallbone and her colleague said RIPK1 inhibition remains “a new treatment paradigm in this space.”