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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? Key Learnings: • There are four U.S. Food and Drug Administration (FDA)-approved agents (ibrutinib, belumosudil, ruxolitinib, and axatilimab) for the treatment of SR chronic GvHD, all indicated for use in the second or third line of therapy. • Optimal sequencing of these agents remains a significant challenge for clinicians, particularly as advances in the therapeutic landscape now allow earlier assessment of treatment response, with novel agents showing efficacy within approximately 8 weeks, compared with 3–6 months for older treatments, enabling more timely transitions to alternative therapies when needed. • Another key challenge is selecting the most appropriate initial therapy; expanded access to biomarkers or other biologic information that can accurately predict response to specific agents could address this gap. o Furthermore, markers that can predict response after therapy has been initiated, such as increases in regulatory T cells observed with interleukin-2 or belumosudil, may prove helpful. • However, predictive biomarkers to guide therapy prior to treatment initiation are still limited and, in such cases, most clinicians rely on clinical features to guide treatment choice. • Safety and tolerability of the drugs are also critical in treatment selection, as each drug has a unique side-effect profile that may restrict its use in some patients. • Balancing efficacy, safety, and patient quality of life remains central to treatment selection. 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.