Approved and emerging therapies for glucocorticoid-refractory chronic graft-versus-host disease

Abstract

Glucocorticoid-refractory chronic graft-versus-host disease (glucocorticoid-refractory cGVHD) remains a major barrier to long-term survival and quality of life following allogeneic hematopoietic stem cell transplantation (allo-HSCT), affecting 30–70% to half of patients with chronic GVHD who fail corticosteroid therapy. In recent years, the Food and Drug Administration (FDA) has approved four agents — ibrutinib, ruxolitinib, belumosudil, and axatilimab — each targeting distinct immune and fibrotic pathways. This review systematically evaluates their mechanisms of action, efficacy across organ systems, and safety profiles while highlighting persistent limitations. We further summarize emerging therapies in clinical and preclinical development, including kinase inhibitors, monoclonal antibodies, cellular approaches, and tissue-specific interventions. A dual-axis framework — distinguishing inflammatory versus fibrotic phenotypes and organ-specific manifestations — is proposed to support biomarker-guided, individualized treatment. In addition, combination regimens and AI-assisted strategies offer new opportunities to optimize outcomes and reduce treatment burden. Despite these advances, challenges remain, including irreversible fibrosis, disease heterogeneity, lack of standardized diagnostic criteria, and balanced GVHD and graft versus tumor effect. Greater incorporation of patient-reported outcomes and long-term functional assessments into clinical trials and practice is urgently needed. Collectively, this review offers a roadmap for optimizing glucocorticoid-refractory cGVHD management, and evolving strategies hold promise for transforming glucocorticoid-refractory cGVHD from a life-limiting condition into a manageable chronic disease.