cGvHD: Answering the unanswered

During the GvHD Hub Steering Committee meeting on November 26, 2024, Steven Pavletic chaired a quick-fire discussion on: Answering the unanswered in chronic graft-versus-host disease (cGvHD). The discussion featured contributions from Mohamad Mohty, Ali Bazarbachi, Hildegard Greinix, Florent Malard, Mutlu Arat, and Arnon Nagler.

Pavletic opened by describing the decrease in cGvHD incidence over recent years, although challenges remain. Prednisone is still a first-line therapy, and there is a lack of consistent guidance on subsequent therapy sequencing, which can make it difficult for physicians to select second- and third-line treatments. The more recently approved therapies for cGvHD illicit mostly partial responses, with complete response observed in only 5–10% of patients. Following this introduction, the steering committee covered the following:

How to choose the right drug for the right patient?

• Currently, drug selection is trial-and-error, revealing a need to explore alternatives to first-line prednisone; the recent approvals of ruxolitinib, belumosudil, and axatilimab in steroid-refractory cGvHD may enable new drugs to be combined with prednisolone for improved outcomes.
• Extracorporeal photopheresis (ECP) may be able to be utilized in patients without prior or concurrent therapies, for example in sclerodermatous manifestations of cGvHD, alongside ruxolitinib.

How to elicit high rates of complete response?

• Assessment of response remains complex due to organ-specific variability, partial responses, and pre-existing damage, and current criteria may not fully capture improvements, especially for challenging organs such as the skin.​
• Better tools are needed to evaluate skin and joint responses effectively, and patient-reported outcomes are critical, particularly with sclerotic skin and joint involvement.​
• Combination therapies targeting different aspects of GvHD pathophysiology may improve outcomes, but toxicity remains a concern; strategies such as reduced or alternate dosing could mitigate risks.​

How to choose timing when tapering immunosuppressive agents​​?​

• Tapering of immunosuppressive agents remains a significant challenge due to variability in clinical practices, and concerns for disease flare-ups may contribute to hesitancy in tapering; early aggressive treatment with novel agents such as ruxolitinib and belumosudil alongside steroids may optimize outcomes.​
• Implementing steroid-free regimens can be challenging, with inconsistent responses and trial enrollment barriers; future approaches should focus on identifying reliable biomarkers and utilizing well-tolerated therapies that can be safely maintained long-term to balance efficacy and side effects.​

How to treat bronchiolitis obliterans syndrome?​

• Early diagnosis of bronchiolitis obliterans syndrome (BOS) through regular pulmonary function tests, and proper workup when FEV1 decreases, is important. Regular pulmonary function tests during the first year are vital for the early detection of BOS, with early identification enabling timely treatment; additional tests should be conducted for patients with viral or pulmonary infections to ensure BOS is detected early and managed effectively. ​
• Efficient initial treatments have shown promise in reversing BOS, although salvage strategies are more complex and less effective.​ Using combinations of first-line therapies such as belumosudil plus ruxolitinib could improve outcomes, but there is a need for clinical trials to validate these combinations.​
• High response rates to drugs such as ruxolitinib and inhaled steroids have been observed in patients with early-stage BOS; however, timely diagnosis remains a challenge since symptoms often emerge late.​

How to rationally choose drug combinations?​

• Combining drugs with different mechanisms or at lower doses to avoid overlapping toxicities may increase efficacy, but evidence remains limited and there is a need for pre-clinical investigations to better understand rational drug combinations.​

Why do some patients get infections and others do not​​?​

• B-cell dysfunction, particularly low memory B-cell counts, is a major factor contributing to infection susceptibility, and distorted B-cell populations are notably worse in patients with BOS than those with other organ manifestations.​
• Infections remain the leading cause of death in patients with cGvHD, underscoring the need for further research.​

How do we diagnose and treat atypical manifestations of cGvHD?​

• Atypical manifestations of cGvHD (e.g., lung, kidney, serositis) are gaining recognition, but real-world data and evidence-based treatments are lacking; these manifestations are often associated with impaired survival.​

Why haven’t biological studies provided better insights for clinical use?​

• Barriers include a lack of translational success from biological studies to clinical applications, and challenges in conducting and scaling clinical trials to test drug combinations.

Why don’t we have biomarkers for clinical use in cGvHD?​

• While there has been progress in biomarker identification for acute GvHD, cGvHD remains complex due to its prolonged trajectory, confounding factors, and diverse treatment regimens. Most biomarkers identified (e.g., CD19+ CD21− subsets) are diagnostic, with limited predictive or response-monitoring utility.​

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.