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

Area of Science:

• Hematology and Immunology
• Oncology
• Pharmacology

Background:

• Glucocorticoid-refractory chronic graft-versus-host disease (cGVHD) significantly impacts survival and quality of life after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
• This condition affects a substantial portion of patients who do not respond to standard corticosteroid therapy.

Purpose of the Study:

• To systematically review recently approved therapies for glucocorticoid-refractory cGVHD, including their mechanisms, efficacy, and safety.
• To summarize emerging treatments and propose a framework for individualized, biomarker-guided management.
• To highlight ongoing challenges and future directions in optimizing cGVHD care.

Main Methods:

• Systematic evaluation of four FDA-approved agents (ibrutinib, ruxolitinib, belumosudil, axatilimab) targeting distinct pathways.
• Review of emerging therapies in clinical and preclinical development.
• Proposal of a dual-axis framework (inflammatory vs. fibrotic phenotypes, organ-specific manifestations) for personalized treatment.

Main Results:

• Four targeted agents have been approved, addressing specific immune and fibrotic pathways in cGVHD.
• Combination regimens and AI-assisted strategies show promise for improved outcomes and reduced treatment burden.
• Persistent challenges include irreversible fibrosis, disease heterogeneity, and balancing GVHD with graft-versus-tumor effects.

Conclusions:

• Advances in targeted therapies and personalized approaches offer a roadmap for optimizing glucocorticoid-refractory cGVHD management.
• Future strategies aim to transform cGVHD into a manageable chronic condition, emphasizing patient-reported outcomes and functional assessments.
• Addressing disease heterogeneity and fibrosis remains critical for improving long-term survival and quality of life post-allo-HSCT.