Chronic Graft-versus-Host Disease: A Review of Current Treatments beyond Second-Line and Emerging Therapies

BACKGROUND: Chronic graft-versus-host disease (cGVHD) remains a major cause of late morbidity and non-relapse mortality following allogeneic hematopoietic cell transplantation. Early identification and intervention are critical to improving outcomes. Corticosteroids continue to serve as the first-line therapy; however, treatment-refractory cases are common and associated with poor outcomes. Ruxolitinib has become the standard second-line agent, yet beyond ruxolitinib, treatment selection varies widely due to a lack of comparative data and standardized sequencing strategies. A comprehensive review of key therapeutic trials in chronic GVHD was conducted, with a focus on second-line treatments and beyond. Emerging and investigational therapies were also included through analysis of recent literature and ongoing studies. SUMMARY: There is currently no established sequencing of agents beyond second-line therapies. The approval of belumosudil, axatilimab, and ibrutinib has expanded therapeutic options, with each agent offering a unique mechanism of action and demonstrating promising organ-specific response rates. KEY MESSAGES: The therapeutic landscape for chronic GVHD is evolving, with several newer agents beginning to demonstrate utility in third-line settings. However, the selection of third-line agents remains largely dependent on clinical judgment, prior treatment history, and the specific organs involved. There is a continuing and critical need for well-designed, comparative trials to establish optimal treatment strategies.