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

Key Takeaways

  • Current challenges in the treatment of graft-vs-host disease (GVHD) include the need to treat the disease with an immune suppressive approach that leads to significant side effects. Disease management is also hampered by the inability to customize treatment to the patient and by the relatively high number of patients who fail to achieve a complete response with treatment or who lose their response over time.
  • Researchers are currently investigating whether biomarkers that indicate disease risk could guide therapeutic decisions.
  • Current studies are also being conducted to determine whether the use of corticosteroids as a first-line treatment could be reduced or replaced by newer drug combinations, but none are yet at a stage where they would change current clinical practices except for the use of sirolimus in standard-risk acute GVHD (aGVHD).

From December 10 to December 13, 2022, hematologists gathered in New Orleans and virtually at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. The 2022 meeting included a wide range of education and scientific sessions and symposia, along with posters and e-posters discussing the latest research, insights, and innovations in the treatment of chronic and acute GVHD, including in steroid-refractory settings.
Doris M. Ponce, MD, who is a hematologic oncologist, associate attending physician, and program director of GVHD at Memorial Sloan Kettering Cancer Center in New York City, shared her insights from the 2022 ASH Annual Meeting and Exposition.

What are some of the current treatment challenges for patients with aGVHD, especially in the steroid-refractory setting?  

A challenge for patients with GVHD is that the main current treatments are based on an immune suppressive approach, where patients are exposed to high-dose systemic corticosteroids, which cause significant side effects. Additionally, they might not achieve a complete response. Recent data suggests that with treatment-naive GVHD, response rates can vary from 40% to 60%, according to their disease risk stratification.1 For those patients who do not respond to therapy, treatment needs to be escalated. Currently, the only treatment that is approved by the US Food and Drug Administration (FDA) for steroid-refractory acute GVHD (SR-aGVHD) is ruxolitinib, so patients are usually treated in combination with corticosteroids; still, not all achieve a complete response. We also have a group of patients who will lose their response to pharmacotherapy over time. Thus, some of the challenges are to try to minimize exposure to systemic corticosteroids, improve treatment responses, and consider approaches that allow the patient to have a more customizable treatment.

In the era of precision medicine, wherein therapy is targeted to the patient, can you comment on biomarker-guided therapeutic decision making in SR-aGVHD?

Acute GVHD biomarkers are a novel and emerging field in bone marrow transplant, and current data have provided us very interesting tools to assess for GVHD. The most widely used biomarker guidance is the Ann Arbor algorithm, which uses 2 biomarkers: suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α).2 The measurement of these 2 biomarkers provides a number that allows us to classify the patient into low, intermediate, or high risk, independent of their clinical status and based on the likelihood of GVHD lethality and non-relapse mortality (NRM). As of right now, biomarkers have not been used for therapeutic decisions; however, the MAGIC trial ( identifier: NCT05090384) is currently doing a phase 2 study for pediatric patients with Minnesota standard GVHD risk that are also Ann Arbor 1 by biomarkers, which is a very low risk category. They are receiving treatment with a low dose of corticosteroids of 0.5 mg/k, and the taper is done quickly on a weekly basis if there is a clinical response and favorable biomarker scores, with the primary endpoint of severe infections. This research highlights that a biomarker-driven approach could be an important tool in identifying patients who could respond to a lower dose of steroids.

Some of the challenges with GVHD are to try to minimize exposure to systemic corticosteroids, improve treatment responses, and consider approaches that allow the patient to have a more customizable treatment.

Can you discuss the findings related to a presentation evaluating the addition of ruxolitinib to corticosteroids for high-risk aGVHD in allogeneic peripheral blood stem cell transplantation?3 Would you consider these results compelling enough to warrant designating this combination as first-line therapy for newly diagnosed aGVHD? 

The results were compelling and they complement a strong story about how critical it is to provide adequate treatment for patients who have high-risk disease. However, I still would not use these results to initiate a practice change because I did not agree with parts of the study design. Patients were treated with 1 mg/k/d instead of 2 mg/k/d of corticosteroids in the experimental arm, and the dose of ruxolitinib was only 5 mg/d, which is suboptimal.3
Still, the concept of treating patients with high-risk GVHD with an additional drug besides corticosteroids is something that is currently being investigated nationwide in our phase 3 study ( identifier: NCT04167514) using a different drug — alpha-1 antitrypsin. So this concept is novel and we are exploring it, but based on the data from this study, we need to learn more and work with a patient population that reflects a true high-risk group. The treatment should also follow what we currently do in practice in terms of the dose of corticosteroids and ruxolitinib if we really wish to take those results and apply them in practice. 

Your recent research revealed that recombinant human interleukin-22 (IL-22) promotes epithelial regeneration and induces innate antimicrobial molecules in patients with gastrointestinal aGVHD.4 Can you further elaborate on the role of combining immunosuppressive therapy with therapy to address epithelial regeneration and mucosal healing?

Our study ( identifier: NCT02406651) tested IL-22, which is a cytokine associated with promotion of epithelial regeneration and induction of innate antimicrobial molecules. We conducted a phase 2 study combining IL-22 with systemic corticosteroids for the treatment of lower gastrointestinal aGVHD. Our primary objective was day 28 treatment response, and the results were positive. However, I cannot prove to you that it promoted epithelial regeneration based solely on the overall clinical response. Nonetheless, a small subset of patients underwent gastrointestinal biopsies at baseline and post-therapy and showed signs of epithelial regeneration. Additionally, from what we have seen in mice models, we hypothesize that IL-22 has that effect. The rationale of the study is that IL-22 promotes epithelial regeneration and is complimentary to the healing process in GVHD. Thus, corticosteroids decrease the inflammatory cascade, whereas IL-22 promotes tissue regeneration in the gastrointestinal tract. Additionally, IL-22 is a potent inducer of antimicrobial molecules, including REG3 and mucins. Thus, we investigated the effect of IL-22 in the microbiome health of a subset of patients and observed that patients who responded to therapy had a signal of microbiome recovery that was not observed in the controlled cohort used for comparison from historical data.4 These results open the way for the concept that complimentary treatment besides corticosteroids has a potential role in patients with aGVHD, and it also supports the concept of customizing treatment according to how organs are affected.

Patients with severe gastrointestinal SR-aGVHD have a reduced response rate to ruxolitinib as a second-line therapy, and early access programs suggest fecal microbiota transplant (FMT) can provide a safe and effective treatment option.5 Can you discuss the role that FMT may play as a therapeutic option for severe SR-aGVHD?

FMT has been investigated as a treatment for patients who have failed systemic corticosteroids and need an additional line of therapy. This is an emerging field used specifically in lower gut GVHD, and the data we saw was quite compelling. It highlights that microbiome manipulation and restoration has a role in the treatment of GVHD. Nonetheless, FMT might be a treatment for patients who have exhausted front-line and second-line therapies. Thus, it is unlikely to replace ruxolitinib, but it might be complementary as we learn more about this field.

Differing combinations of the 3 FDA-approved oral drugs for chronic GVHD — either with each other or with other therapies such as extracorporeal photopheresis (ECP), sirolimus, or mycophenolate mofetil (MMF) — have yielded encouraging overall response rates for patients in whom 1 to 2 lines of prior therapy have failed.6 How can clinicians determine which combined therapies would deliver best results for an individual patient?

Ibrutinib, ruxolitinib, and belumosudil have been approved for the treatment of chronic GVHD; however, the combination of these 3 agents is not approved. Ibrutinib and ruxolitinib are both approved for second-line therapy after failure of steroids for chronic GVHD, and belumosudil is approved for third-line therapy or beyond. Clinically, we have combined ruxolitinib and belumosudil in a setting of tapering ruxolitinib and introducing a new drug without a washout period. ECP has the advantage of not causing immunosuppression, and I have seen ECP combined with sirolimus, as we know sirolimus does not affect regulatory T-cell reconstitution, which is ideal in order to induce tolerance.

This Q&A was edited for clarity and length.


Doris M. Ponce, MD, reported affiliations with CareDx, Evive Biotechnology Shanghai Ltd (formerly Generon [Shangai] Corporation Ltd), Gerson Lehrman Group, Ceramedix, Guidepoint Global Advisors, Incyte Corporation, and Kadmon-Sanofi Holdings, Inc.


1. Hill L, Alousi A, Kebriaei P, Mehta R, Rezvani K, Shpall E. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol. 2018;9(1):21-46. doi:10.1177/2040620717741860
2. Hartwell MJ, Özbek U, Holler E, et al. An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight. 2017;2(3):e89798. doi:10.1172/jci.insight.89798
3. Dou L, Zhao Y, Deng L, et al. Addition of ruxolitinib to corticosteroids as first-line therapy for high-risk acute graft-vs-host disease in allogeneic peripheral blood stem cell transplantation. Poster presented at: American Society of Hematology Annual Meeting and Exposition; December 11, 2022; New Orleans, LA.
4. Ponce DM, Alousi AM, Nakamura R, et al. A phase 2 study of Interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract. Blood. Published online November 18, 2022. doi:10.1182/blood.2021015111
5. Malard F, Loschi M, Cluzeau T, et al. Pooled fecal allogenic microbiotherapy for refractory gastrointestinal acute graft-versus-host disease: results from the early access program in France. Poster presented at: American Society of Hematology Annual Meeting and Exposition; December 10, 2022; New Orleans, LA.
6. Chin M, Shizuru JA, Muffly L, et al. Belumosudil combination therapy in refractory chronic graft-versus-host disease. Poster presented at: American Society of Hematology Annual Meeting and Exposition; December 10, 2022; New Orleans, LA.

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

Reviewed January 2023