What are the treatment options for chronic GvHD-associated fibrosis?

The GvHD Hub was pleased to speak with Corey Cutler, Dana-Farber Cancer Institute, Boston, US. We asked, What are the treatment options for chronic GvHD-associated fibrosis?

In this interview, Cutler discusses the development and clinical impact of fibrotic manifestations in chronic graft-versus-host disease (cGvHD), and explores the U.S. Food and Drug Administration (FDA)-approved therapies, including ibrutinib, ruxolitinib, belumosudil, and axatilimab, and the differences in their mechanisms of actions that may influence their use in the treatment of fibrotic disease. He also considers how novel antifibrotic agents might be integrated into the management of fibrotic cGvHD in the future.

Key learnings

• cGvHD following allogeneic hematopoietic stem cell transplantation is a highly heterogenous disease that can lead to severe, debilitating manifestations driven by progressive fibrosis;^1,2 the skin is the most affected organ system, with fibrotic manifestations including fasciitis and scleroderma-like changes.^3,4
• Fibrosis can also occur at the microscopic level, including in the lacrimal and salivary glands, and represents the end stage of the inflammatory process observed in cGvHD.^5–7
• Although advances in graft-versus-host disease (GvHD) prophylaxis have reduced the incidence of cGvHD, including sclerotic cGvHD, it remains a notable issue for many patients, and treatment for fibrotic manifestations is required.^2,8
• Four agents are currently approved by the FDA for the treatment of cGvHD: ibrutinib, belumosudil, ruxolitinib, and axatilimab; and, while there are no head-to-head data to establish superiority in the management of fibrotic disease, the distinct mechanisms of action of individual agents may guide treatment selection in fibrotic cGvHD.²
• Ibrutinib is a Bruton’s tyrosine kinase and interleukin (IL)-2 inducible tyrosine kinase inhibitor that has been shown to decrease inflammatory and fibrotic factors – including epidermal growth factor and granulocyte-macrophage colony-stimulating factor – in patients with cGvHD.^2,9
• Janus kinase (JAK) 1 and 2 signaling is crucial in the steps leading to inflammation and tissue damage in GvHD; ruxolitinib, a JAK1/2 inhibitor, reduces the release of pro-inflammatory cytokines, donor T-cell infiltration into GvHD target organs, and allogeneic T-cell proliferation.^10,11
• Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) signaling promotes the differentiation of fibroblasts into myofibroblasts and stimulates transforming growth factor β (TGF-β)-induced fibrosis. It is further linked to fibrosis, collagen type I production, and the development of cellular adhesion, through direct and indirect effects on macrophage function.^12,13
  • Belumosudil targets the ROCK2 pathway and downregulates and reverses fibrosis via several mechanisms including inhibition of actin polymerization, suppression of proinflammatory cytokines, and inhibition of profibrotic gene expression and TGF-β signaling. This results in blockade of fibroblast differentiation into myofibroblasts and collagen production, demonstrating intrinsic anti-fibrotic activity.¹²
• Axatilimab is a monoclonal antibody targeting the colony-stimulating factor 1 receptor (CSF-1R). CSF-1R is expressed on macrophages – key inducers of fibroblast growth factors – which in turn promote fibrotic disease.¹⁴
  • Axatilimab treatment has been shown to inhibit production of inflammatory and pro-fibrotic factors by pro-inflammatory macrophages, demonstrating that axatilimab may prevent fibrosis in cGvHD.¹⁴
• Due to their mechanism of action, it is thought that belumosudil and axatilimab may be particularly effective for the treatment of fibrotic manifestations of cGvHD; clinical trials are ongoing to evaluate both of these agents in this setting, although results from these trials are not currently available.^15,16
• Emerging antifibrotic agents, including those without anti-inflammatory activity, are being evaluated and considered for integration into the management of fibrotic cGvHD.

This educational resource is independently supported by Sanofi. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.