Doris M. Ponce, MD
Memorial Sloan Kettering Cancer Center
New York, NY

Key Takeaways

  • 50% to 60% of patients with high-risk acute graft-vs-host disease (GVHD) do not respond to treatment with corticosteroids.
  • Ruxolitinib is the only approved treatment for steroid-refractory acute GVHD.
  • Gut microbiota dysbiosis is frequently observed in patients with gastrointestinal (GI) steroid-refractory GVHD, creating opportunities for new therapies.
  • Future treatment will likely involve strategies that combine immunosuppression and other agents, such as regenerative or tissue-repair adjunct therapies, to improve treatment response.

Doris M. Ponce, MD, is a hematologic oncologist and clinical researcher at Memorial Sloan Kettering Cancer Center, in New York. She has expertise in hematopoietic stem cell transplantation (HSCT), and her research focuses on strategies to prevent and treat GVHD and to make transplantation safer and more effective.

What is the burden of GVHD on patients with a hematologic malignancy?

Most blood disorders occur in the elderly. The growth of the population 65 years of age and older is unprecedented; therefore, we see more cases of hematologic malignancy in these patients. Treatment with HSCT can be curative for advanced hematologic malignancies and is performed in children and adults, including older adults.
The presence of GVHD is a significant burden on morbidity, survival, and quality of life. An estimated 30% to 60% of patients develop GVHD during transplantation. As HSCT activity increases globally every year, and as we have more racially diverse patients, more transplantations are performed with human leukocyte antigen-mismatched donors, which increases the risk of acute GVHD.
The upfront therapy for acute GVHD is systemic corticosteroids, but approximately 50% of patients do not respond to this treatment and others lose their response over time. A treatment response of 70% to 80% has been seen in patients at standard risk, and a response rate of approximately 50% has been seen in those at increased risk. Furthermore, patients with acute GVHD of the gut are less likely to remain responsive to upfront therapy.

What is known about the pathogenesis of steroid-refractory GVHD (SR-GVHD)?

It is not known exactly why some patients respond to initial treatment with a corticosteroid and why some do not, but we have signals that help predict which patients will, and which will not, respond.
The Minnesota Acute GVHD Risk Score1 classifies patients with GVHD as standard or high risk and can predict treatment response. Patients with high-risk GVHD include those who have:

●      Skin stage 4;
●      Lower GI stage 3-4;
●      Liver stage 3-4; and
●      Skin stage 3 and either lower GI stage 2-4 or liver stage 2-4.
The Ann Arbor algorithm2 includes measurement of GVHD biomarkers that can predict nonrelapse mortality at the onset of GVHD, whereas biomarkers measured on Day 7 of GVHD therapy can predict long-term outcomes in SR-GVHD. We have also found that gut microbiome dysbiosis at the time of neutrophil recovery is associated with transplant-related risk of mortality. Notably, the GI tract is affected in more than 80% of patients who develop SR-GVHD.

What treatments are available for SR-GVHD, and what are their limitations?

The Janus kinase 1 and Janus kinase 2 inhibitor ruxolitinib is the only approved treatment for SR-GVHD. The drug decreases inflammatory pathways and improves overall response.
In a prospective, randomized phase 3 clinical trial (REACH3; Identifier: NCT03112603) comparing ruxolitinib to best available therapy in patients with SR-GVHD, ruxolitinib demonstrated an overall response rate of 62%, which was significantly higher than the 39% response rate seen in the  control group (P <.001). However, in the ruxolitinib group, nonrelapse mortality at 18 months was 49% and median overall survival was 11.1 months, which signals that we have room to do better.3

In a prospective, randomized phase 3 clinical trial comparing ruxolitinib to best available therapy in patients with SR-GVHD, ruxolitinib demonstrated an overall response rate of 62%, which was significantly higher than the 39% response rate seen in the  control group (P <.001).

Ruxolitinib adverse effects
Ruxolitinib adverse effects
Adverse effects commonly reported with ruxolitinib include anemia, impaired balance, dizziness, headache, labyrinthitis, Meniere disease, neutropenia, thrombocytopenia, vertigo, and orthostatic dizziness.

You mentioned that microbiome dysbiosis appears to affect treatment response. What therapies are being developed that address the GI tract in patients following HSCT?

Humans have a complex symbiotic relationship with microbes in the gut. When patients go through HSCT, we frequently observe gut microbiome injury. Patients tend to have reduced microbiota diversity in the first 2 weeks following HSCT that tends to recover after neutrophil engraftment. Patients with low gut microbiota diversity have an increased risk of nonrelapse mortality, and intestinal microbiota diversity is an independent predictor of mortality after HSCT.4
In our research, we have found that certain bacteria are protective. For example, patients with GVHD who had an increased abundance of the Blautia genus of anaerobes had a decreased risk of GVHD-related death.5
Fecal microbiota transplantation has shown promise as a way to manipulate the microbiome. This has been tried with success in the refractory setting in small series and trials. This research is just getting started, and we need robust clinical trials to control for variables to make reasonable conclusions. Therefore, we are going to see more solidly designed clinical trials of fecal transplantation in SR-GVHD.
We are finding that recovery of the microbiome might improve response to therapy. It is possible that a healthy microbiome might be beneficial to other organs as well. Improving the microbiome might be upregulating an anti-inflammatory response that could go beyond the GI tract.

What other therapies are in development for SR-GVHD?

We are looking at α1-antitrypsin (AAT), a serine protease inhibitor that increases the ratio of regulatory-to-effector T cells. Patients with GVHD had lower levels of AAT in plasma; the lower the level, the worse the GVHD. The safety and efficacy of AAT in SR-GVHD has been evaluated, and it is now being assessed in a trial for upfront GVHD, focusing on patients with high-risk disease. In a small prospective study of AAT in patients with SR-GVHD, the overall response rate on Day 28 was 65%; at Day 60, 73% of patients had an overall or complete sustained response, without intervening immunosuppression.6
Epidermal growth factor contained in urinary-derived human chorionic gonadotropin is also moving into a phase 2 trial for high-risk patients with GVHD. A phase 1 study found this to be a safe therapy that promotes healing of damaged tissue in high-risk GVHD and SR-GVHD.7

What is the future of treatment for SR-GVHD?

When we look at GVHD, we might see that we need more than 1 drug because there is more than 1 issue to address. We might need to combine immunosuppression with tissue regeneration or other strategies. Plasma or serum biomarkers and microbiome health might help customize therapy for patients with GVHD.
What we do know is that treatment needs to start early. It is difficult to reverse damage if treatment is started at a later stage, and more immunosuppressive drugs get added. We want to minimize exposure to immunosuppression. In clinical trials, we try to minimize how long patients need prednisone because of the adverse effects and complications associated with that treatment. We also put a lot of weight into quality of life in SR-GVHD. These patients are at high risk for nonrelapse mortality because immunosuppression puts them at risk for infection, such as viral reactivation.
Future research needs to look at different treatment modalities that minimize therapy-related complications and improve quality of life without compromising efficacy.

The Q&A was edited for clarity and length.


Doris M. Ponce, MD, reported affiliations with CareDx, Guidepoint Global LLC, Evive Biotech, Gerson Lehrman Group, Kadmon Holdings, Inc., and Slingshot Insights.


  1. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001
  2. Levine JE, Braun TM, Harris AC, et al; Blood and Marrow Transplant Clinical Trials Network. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol. 2015;2(1):e21-e29. doi:10.1016/S2352-3026(14)00035-0
  3. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635
  4. Taur Y, Jenq RR, Perales M-A, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174-1182. doi:10.1182/blood-2014-02-554725
  5. Jenq RR, Taur Y, Devlin SM, et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(8):1373-1383. doi:10.1016/j.bbmt.2015.04.016
  6. Magenau JM, Goldstein SC, Peltier D, et al. α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood. 2018;131(12):1372-1379. doi:10.1182/blood-2017-11-815746
  7. Holtan SG, Hoeschen AL, Cao Q, et al. Facilitating resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor. Blood Adv. 2020;4(7):1284-1295. doi:10.1182/bloodadvances.2019001259

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cancer Therapy Advisor had no role in this content’s preparation.

Reviewed March 2021