In this interview, Cutler discusses the development and clinical impact of fibrotic manifestations in chronic graft-versus-host disease (cGvHD), and explores the U.S. Food and Drug Administration (FDA)-approved therapies, including ibrutinib, ruxolitinib, belumosudil, and axatalimab, and the differences in their mechanisms of actions that may influence their use in the treatment of fibrotic disease. He also considers how novel antifibrotic agents might be integrated into the management of fibrotic cGvHD in the future.

This educational resource is independently supported by Sanofi. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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During his presentation, Zeiser outlined the proposed mechanism of action of MSCs, describing how they promote an immunosuppressive and immunoregulatory environment. He explored the evolving clinical trial landscape of MSCs in the treatment of GvHD, beginning with the first reported use in 2004, and summarized key trial results leading to the approval of the MSC products remestemcel-L and JR-031. Zeiser highlighted the challenge of MSC product variability, which has contributed to heterogenous response rates across studies. He introduced MSC-Frankfurt am Main (FFM), an MSC product generated by pooling bone marrow-derived mononuclear cells from eight human leukocyte antigen (HLA)-disparate donors to reduce variability. He also explored MSC-FFM outcomes across real-world cohorts and presented the study designs of two ongoing phase II/III trials.

This discussion topic is supported by Medac, who provided funding. All content was developed independently by the steering committee in collaboration with SES. Funders were allowed no influence on the content of the discussion.

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Wolff provided an overview of the treatment options for second-line treatment after steroids and subsequent advanced-line options, emphasizing that early detection of disease progression and sufficient treatment intervention are crucial, as advanced disease is often nonreversible. Wolff discussed response assessments to first-line steroid treatment and second-line treatments, and outlined the treatment options for patients with SR-cGvHD, including ruxolitinib, belumosudil, axatilimab, ibrutinib, and extracorporeal photopheresis.

This educational resource is independently supported by Sanofi.​

All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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Pavletic discussed the importance of the assessment of quality of life using patient-reported outcome measures (PROMs) in both clinical trials and clinical practice in cGvHD, outlining the frequently used PROMs in GvHD, including cGvHD-specific and dimension-specific measures. Pavletic highlighted that incorporation of PROMs into standard of care practice may ultimately lead to more tailored and effective clinical assessments.

This educational resource is independently supported by Sanofi. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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In this interview, Mohamad Mohty discusses the evolving management of steroid-refractory acute GvHD, highlighting ruxolitinib as the standard of care and the importance of robust supportive measures. Mohty explores treatment options for ruxolitinib-refractory disease – including extracorporeal photopheresis, mesenchymal stromal cells, and emerging targeted approaches. Mohty highlights the value of referral to specialized centers and clinical trial enrolment as treatment shifts toward precision-guided, biology-driven strategies.

This educational resource is independently supported by Medac. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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Mohty provided an overview of RWD, including their use in regulatory decision-making, types of RWD, study designs, and limitations. Mohty explored whether results of pivotal clinical trial results can be reproduced with RWD, highlighting the consistent outcomes observed in a French compassionate use program of belumosudil.

This educational resource is independently supported by Sanofi.

All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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In this interview, Zeiser explores the current treatment options for SR-cGvHD, such as ruxolitinib, ibrutinib, belumosudil, and axatilimab, and discusses the different mechanisms of action involved in targeting distinct pathways involved in cGvHD pathogenesis. Zeiser notes that future directions may focus on identifying optimal combination therapies for patients with SR-cGvHD.

This educational resource is independently supported by Sanofi. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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The GvHD Hub spoke with Corey Cutler, Dana-Farber Cancer Institute, Boston, US. We asked, What are the major challenges in the treatment of steroid-refractory GvHD (SR-GvHD), and how can clinicians overcome these?

This educational resource is independently supported by Sanofi. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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Mohty began by explaining the necessity of measuring QoL in patients with graft-versus-host disease (GvHD) and the current use of PROs in trials and clinical practice. During the discussion, the steering committee members provided insight into the difficulties implementing QoL assessment in clinical practice, and potential solutions.

This independent educational activity is supported by Sanofi. All content was developed independently. The funder was allowed no influence on the content of this activity. 

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Gagelmann began by presenting the design and rationale of a real-world retrospective study in Germany, response and survival outcomes, and key takeaways. During the discussion, the steering committee members provided their thoughts on the use of combination therapies, specifically ECP + ruxolitinib, in SR-GvHD, and potential directions for future studies.  

This independent educational activity was supported by Therakos. All content was developed independently. The funder was allowed no influence on the content of this activity. 

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The GvHD Hub spoke to Steven Pavletic, National Cancer Institute, Bethesda, US, about his perspectives on how RWE can complement RCTs, and why it may be important for small patient populations. 

RCT vs RWE 

• Data from RCTs are considered the ‘gold-standard’ for investigating the efficacy and safety of treatments, owing to the well-controlled, observational environment, with strict inclusion and exclusion criteria. 
• A major challenge with RCT data is that they generally apply to a specific population of patients but may not be relevant for all individuals with the disease.  

Ideally, RCTs and real-world studies should be developed to be complementary. For example, if an RCT investigates the efficacy of a drug, the real-world studies can focus on the epidemiology, effectiveness, safety, or costs of treatment related to that drug. 

Real-world data in cGvHD 

• cGvHD is heterogeneous in presentation, with variability in severity, organ involvement, and manifestations. 
• It is important to identify less common adverse effects that may result from treatment in patients with varied clinical manifestations of cGvHD, which is not always possible in clinical trials. 
• Therefore, further RWE and observational studies are needed to provide additional data on the safety and efficacy of treatments, particularly in cGvHD which can have distinct patient populations. However, these studies lack the consistency of RCTs, and caution should be used when interpreting results. 
• Several recent prospective phase II/III studies have led to the approval of new agents for cGvHD, including ibrutinib, ruxolitinib, and belumosudil. In the case of belumosudil, real-world studies have consistently shown safety and effectiveness similar to the RCTs, which is encouraging for the broader cGvHD patient population. 
• Both RWE and RCTs can be helpful tools for advancing clinical research and informing patient care, especially when considered together. 

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Mesenchymal stromal cells (MSCs) have emerged as a potential therapy option in patients with steroid-refractory graft-versus-host disease (SR-GvHD).1 MSCs do not express human leukocyte antigen class II and can therefore be administered without the need for matching, giving them a distinct advantage over other cellular therapies.

The GvHD Hub spoke to Robert Zeiser, Medical Center—University of Freiburg, Freiburg, DE, about his key insights into MSCs for aGvHD, and the current clinical trial landscape.  

The MSC clinical trial landscape  

• The first patient treated with MSCs, in 2004, experienced improvements in gastrointestinal and hepatic manifestations of severe GvHD after infusion of haploidentical MSCs. Since then, there have been multiple studies investigating MSCs as a potential treatment in aGvHD, although not all trials have met their primary endpoint. 
• In general, MSCs are well tolerated by patients, with promising efficacy demonstrated in clinical trials; however, there is some variation in response rates. 
• The mechanism of action of MSCs is still unclear; current evidence suggests that intravascular MSC destruction is followed by monocyte-mediated immune modulation, with monocytes playing a key role in the efficacy of the treatment. 

Recent developments 

• Remestemcel-L-rknd, an allogeneic bone marrow-derived MSC therapy, was approved by the U.S. Food and Drug Administration (FDA) on December 18, 2024, for the treatment of steroid-refractory acute graft-versus-host disease (aGvHD) in pediatric patients (aged ≥2 months). 
• Another allogeneic MSC product, Mesenchymal Stromal Cells-Frankfurt am Main (MSC-FFM), is currently being investigated in the phase III IDUNN trial (NCT04629833) across multiple centers in Europe. The trial will compare MSC-FFM to the best available therapy in patients with SR-aGvHD. This therapy differs from other MSC products, as it is made from pooling cells from multiple donors rather than a single donor, and is already available for use in Germany under Hospital Exemption.

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View on the GvHD Hub here: https://gvhdhub.com/medical-information/future-perspectives-of-ecp-for-gvhd-treatment

Gennery begins by providing a background to using ECP in pediatric patients, including the potential complications involved and how to mitigate these. He then discusses the process of ECP, including treatment scheduling, and its efficacy in different types of GvHD. 

Gennery goes on to speak about how the treatment landscape for GvHD has changed in the last 5 years, how it might change in the future, and where ECP fits in as an immunomodulatory agent. In the future, ECP may be combined with the newer immunosuppressive agents that are approved, or in development, for the treatment of GvHD to deliver positive outcomes for patients.

This independent educational activity was supported by Mallinckrodt Pharmaceuticals. All content was developed independently by the faculty. The funder was allowed no influence on the content of this activity. 

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Zinaida Perić, University of Rijeka, Rijeka, HR, shared her thoughts on patient eligibility, treatment optimization, and follow-up after treatment with ECP for cGvHD. She also discussed a case report of a patient with steroid-refractory (SR)-cGvHD, plus retrospective and prospective data on the use of ECP in cGvHD. In addition, she shared the Nordic ECP Quality Group treatment guidelines for SR-cGvHD.

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Here, we share the presentation by Florent Malard, Hôpital Saint-Antoine and Sorbonne Université, Paris, FR, that explored early intervention and ECP-based combinations. Mallard covered use of ECP first-line, as well as ECP combinations in patients with steroid-refractory and steroid-dependent cGvHD, including recent approvals and findings from clinical trials.

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Here, we share the presentation by Bipin Savani, Vanderbilt University Medical Center, Nashville, US, which explored the long-term burden of cGvHD. Savani discussed organs frequently affected by cGvHD, comorbidities and mortality in patients with cGvHD, and recent progress made in improving the safety of transplantation. He highlighted that mental health disorders, such as anxiety and depression, are prevalent in patients with cGvHD and that the physical burden of symptomscontributes to limitation of daily activities in these patients. 

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Here, we share the presentation by Mohamad Mohty, Hôpital Saint-Antoine and Sorbonne Université, Paris, FR, which explored a brief history of ECP, outlined the allogeneic hematopoietic stem cell transplantation and ECP procedures, and also included two cGvHD patient case studies.

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Professor Alousi opens by highlighting the importance of supportive care in GvHD and the challenges in ensuring this is delivered effectively. This discussion focusses on the side effects and adverse events associated with GvHD treatments, including those that may have a negative impact on a patient’s quality of life.

The steering committee members discuss the need for a multidisciplinary approach to GvHD treatment through communication with other healthcare professionals (HCPs). For example, mental health professionals, pharmacists, and ophthalmologists may all be involved in the treatment of a patient with GvHD depending on the manifestation of the disease. The discussion concludes that cross-functional collaboration of HCPs may have a positive impact on quality of life and requires further research.

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Socié begins by highlighting the main differences between aGvHD treatment in the EU and in the US. Socié then discusses the use of steroids in aGvHD treatment, despite 40–50% of patients becoming steroid-resistant. Finally, Socié talks about the current standard of care in steroid-resistant aGvHD.

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Savani begins by highlighting the importance of supportive care for patients with GvHD. Perić then discusses how, if local therapy is effective enough, systemic treatment can be avoided, and how there should always be an aim to use the least immunosuppression possible. Savani goes on to talk about pain and fatigue management in these patients and how physical therapy could play a role. Finally, both Perić and Savani emphasize that supportive care should be a priority, and more data on the use of physical exercise and therapy is key to improving the quality of life for patients with GvHD.

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Weisdorf begins by discussing the Minnesota Risk Score (M. MacMillan, et al.), which uses the stage of skin, liver, and gut involvement in GvHD to predict the response to therapy. Weisdorf then talks about the potential of incorporating biomarkers into the Minnesota Risk Score in the future.

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In this podcast, Mohty highlights the latest advances in the field of steroid-refractory acute GvHD and emphasizes the importance of prevention, commenting on anti-thymocyte globulin (ATG), allogeneic hematopoietic stem cell transplant (allo-HSCT), and posttransplant cyclophosphamide. Mohty also mentions the HERACLES trial (NCT03225937) and the use of the JAK inhibitor ruxolitinib. 

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The main topic of this podcast is about documenting the quality of life (QoL) of patients with acute and chronic GvHD. Lachance focuses on patient-reported outcomes regarding the impact GvHD has on aspects of daily life. Research has demonstrated that GvHD severity, long term corticoid treatment, or being corticoid resistant have a significant impact on QoL.

Hamad continues the conversation by exploring the stress of survival for patients undergoing bone marrow transplantation. She believes that patient self-reported symptoms should direct future research on GvHD treatment and prevention. 

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In this podcast, Dr Davar starts by providing a background on the importance of the microbiome in adaptive and innate immunity, while Dr Spencer states the importance of the cross-talk between the microbiome and immune system through microbial products, peptides, and metabolites. Dr Davar then explains the concept of immunosurveillance, immunoediting, and checkpoint inhibitors. Dr Spencer describes fecal microbiome transplant studies that showed features of the microbiome can predict response to immunotherapy and effect T-cell expression. Dr Davar then describes some of the studies that are looking at fecal microbiome transplant in combination with checkpoint inhibitors. He goes on to discuss studies investigating the use of live bacterial products to elicit the same effects as fecal microbiome transplant, particularly the mediation of CD8 T cells. Dr Spencer also talks about probiotics, antibiotics, and diet and explains how this can affect the gut microbiome and describes studies looking at these features in terms of response to immunotherapies. She also describes the microbiome research related to graft-versus-host-disease and the impact of higher alpha diversity on post-transplant survival, while Dr Davar explains how the microbiome may also affect toxicity and side-effects of cancer immunotherapies. 

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