Chronic graft-versus-host disease: Update on pathobiology, biomarkers, and evolving treatment algorithms

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and disability post-allogeneic hematopoietic cell transplantation (allo-HCT).
• Current treatments often involve toxic corticosteroids, necessitating advances in therapeutic strategies.
• Understanding cGVHD pathogenesis is crucial for developing targeted interventions.

Purpose of the Study:

• To review current mechanistic insights and clinical evidence for cGVHD.
• To align contemporary biomarkers with the three-phase pathogenesis model of cGVHD.
• To discuss how approved agents target phase-specific pathways and propose a risk-stratified treatment algorithm.

Main Methods:

• Synthesis of current mechanistic insights and clinical evidence on cGVHD.
• Framework based on the three-phase pathogenesis model: early inflammation, impaired tolerance, and fibrosis/end-organ damage.
• Exploration of biomarkers (ST2/CXCL9, BAFF/autoantibodies, MMP3/TGF-β) and FDA-approved agents (ibrutinib, ruxolitinib, belumosudil, axatilimab) in relation to disease phases.

Main Results:

• Biomarkers align with specific phases: ST2/CXCL9 (Phase 1), BAFF/autoantibodies (Phase 2), MMP3/TGF-β (Phase 3).
• FDA-approved agents demonstrate potential for targeting phase-specific pathways.
• Prophylaxis and upfront strategies have significantly reduced cGVHD incidence.

Conclusions:

• A conceptual, risk-stratified treatment algorithm can link cGVHD pathobiology to clinical decision-making.
• Biomarker-guided selection is investigational but complements clinical assessment.
• Therapeutic advances are accelerating, offering new hope for managing cGVHD.