Toward Better and More Effective Clinical Trials for Chronic Graft-Versus-Host Disease

While the incidence of chronic Graft-versus-Host Disease (chronic GVHD) is declining due to advances in prophylaxis and survival is improving due to better supportive care, first-line treatment of chronic GVHD continues to be based on corticosteroids. Numerous attempts to establish more effective or less toxic treatment alternatives have largely failed, likely due to the biological heterogeneity of chronic GVHD and uncontrolled use of systemic corticosteroids, indicating the need for new approaches. The 2020 NIH consensus conference proposed the systematic evaluation of steroid-free initial treatment combining clinical and biological assessment to establish personalized approaches. While the first generation of trials evaluating steroid-free single agent first-line therapy approaches are recruiting, they are still not able to consider the biological heterogeneity of chronic GVHD in deciding therapeutic approaches. To advance the field, we propose a two-stage adaptive trial design starting with an intervention under consideration followed by a replication phase after the first phase has identified candidate clinical features and or biomarker predicting success. For second and subsequent lines of treatment, current treatment decisions regarding the use of the four FDA approved agents are based on the product label or a trial-and-error approach, sometimes in combination regimens despite the lack of prospective data. Future trials and prospective observational studies should focus on the development of predictive markers to provide a biological rationale for sequencing treatment options and to identify synergistic combination treatments. The recently released FDA draft guidance document for developing drugs and treatments in GVHD serves as the starting point for clinical trials planning that should yield results during the next several years.