Chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic haematopoietic cell transplantation. cGVHD has a heterogeneous biology and morbid manifestations, affecting 30-70% of recipients and substantially impairing quality of life and is the leading cause of non-relapse mortality in allo-HCT recipients. This immune-mediated condition arises from complex immune dysregulation involving B cell and T cell activation, regulatory T cell dysfunction, and fibrosis driven by macrophages and fibroblasts. Glucocorticoids remain the first-line treatment; however, ~50% of patients develop steroid-refractory or steroid-dependent cGVHD, necessitating prolonged immunosuppression causing considerable toxicity. Four second-line treatments have been approved by the FDA - ibrutinib, ruxolitinib, belumosudil and axatilimab - targeting B cell signalling, JAK-STAT, ROCK2 and CSF1R pathways, respectively, and emerging therapies such as rovadicitinib show promise. However, substantial challenges persist in cGVHD treatment, including the heterogeneous biology and morbid manifestations (that is, lung and skin sclerosis), drug resistance and suboptimal supportive care. Biomarkers for early diagnosis and personalized treatment remain under investigation. Multidisciplinary care, infection control and psychosocial support are critical to improving quality of life in patients with cGVHD. Future research should prioritize mechanistic insights, antifibrotic therapies and integrating organ-specific interventions to enhance outcomes in patients with cGVHD.