Advances in treatment of chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard first-line therapy; however, many patients develop steroid-refractory or steroid-dependent disease, underscoring the need for more effective and better-tolerated treatments. Ruxolitinib has emerged as the most evidence-supported option for steroid-refractory cGVHD, with the phase 3 REACH3 trial demonstrating higher response rates, durable disease control, and clinically meaningful improvements in symptom burden compared with best available therapy. Belumosudil and axatilimab have also shown encouraging efficacy and safety in heavily pretreated populations. The addition of novel agents to standard corticosteroid-based therapy has been explored in clinical trials. Interest in combination strategies, such as ruxolitinib with extracorporeal photopheresis or belumosudil, is increasing, though prospective studies are required to define their role. Key challenges include optimizing long-term safety, mitigating infectious complications, and preserving the graft-versus-leukemia effect. This review summarizes current therapeutic strategies and discusses evolving treatment algorithms, emphasizing practical considerations in therapy selection. Approaches targeting specific pathogenic mechanisms, combining agents with distinct mechanisms of action, and incorporating biomarker-driven strategies are expected to further improve outcomes and quality of life for patients with cGVHD.