Chronic graft-versus-host disease

Area of Science:

• Immunology
• Oncology
• Transplantation Medicine

Background:

• Chronic graft-versus-host disease (cGVHD) is a significant complication following allogeneic haematopoietic cell transplantation (allo-HCT), affecting 30-70% of recipients.
• It leads to substantial morbidity, impairs quality of life, and is a leading cause of non-relapse mortality in allo-HCT survivors.
• The condition involves complex immune dysregulation, including T and B cell activation, regulatory T cell dysfunction, and fibrosis mediated by macrophages and fibroblasts.

Purpose of the Study:

• To review the current landscape of cGVHD treatment, highlighting challenges and future directions.
• To discuss approved and emerging therapies targeting specific pathways involved in cGVHD pathogenesis.
• To emphasize the need for improved biomarkers, antifibrotic strategies, and multidisciplinary care.

Main Methods:

• Literature review of cGVHD pathogenesis, current treatments, and emerging therapies.
• Analysis of approved second-line treatments (ibrutinib, ruxolitinib, belumosudil, axatilimab) and their targeted pathways.
• Discussion of persistent challenges including disease heterogeneity, drug resistance, and supportive care.

Main Results:

• Glucocorticoids are first-line, but ~50% of patients are steroid-refractory or dependent, requiring alternative immunosuppression.
• Four FDA-approved second-line treatments target distinct pathways: B cell signaling, JAK-STAT, ROCK2, and CSF1R.
• Emerging therapies like rovadicitinib show potential, yet significant challenges in treatment resistance and managing manifestations like lung and skin sclerosis remain.

Conclusions:

• Despite advances, cGVHD treatment faces challenges due to its heterogeneous nature, drug resistance, and the need for better supportive care.
• Further research into mechanistic insights, antifibrotic therapies, and organ-specific interventions is crucial.
• Biomarker development for early diagnosis and personalized medicine, alongside multidisciplinary care, is essential for improving patient outcomes.