What are the current treatment options for steroid-refractory chronic GvHD?

The GvHD Hub was pleased to speak with Robert Zeiser. We asked, What are the current treatment options for steroid-refractory chronic GvHD?

In this interview, Zeiser explores the current treatment options for steroid-refractory chronic GvHD, including ruxolitinib, ibrutinib, belumosudil, and axatilimab, and discusses the different mechanisms of action used to target distinct pathways involved in chronic GvHD pathogenesis. Zeiser notes that future directions focus on identifying optimal combination therapies for patients with steroid-refractory chronic GvHD.

Key learnings

• Chronic graft-versus-host disease (cGvHD) develops in 30–50% of patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT).¹
• The European Society for Blood and Marrow Transplantation (EBMT) recommends corticosteroids for first-line treatment of cGvHD;² when cGvHD does not respond to steroid treatment, this is considered steroid-refractory cGvHD.
• Ruxolitinib is approved by the U.S. Food and Drug Administration (FDA) for patients with cGvHD who have received one or two lines of systemic therapy.¹
  • Ruxolitinib inhibits Janus kinase (JAK) 1 and 2 activation, blocking downstream effects of interferon (IFN)-γ, IL-6, and common γ chain cytokine receptors. JAK1/2 inhibition decreases signal transducer and activator of transcription (STAT)1/3 phosphorylation, resulting in increased regulatory T (Treg) cells and decreased collagen deposition.¹
• Other FDA-approved therapies for cGvHD include ibrutinib, belumosudil, and axatilimab. Mycophenolate mofetil, extracorporeal photopheresis, mTOR inhibitors, proteasome inhibitors, and tyrosine kinase inhibitors are also widely used beyond second-line treatment of steroid-refractory cGvHD.^1,2
• Ibrutinib inhibits Bruton’s tyrosine kinase (BTK), which mediates signal transduction downstream from the B-cell receptor, and therefore blocks activation of B cells. Ibrutinib also inhibits IL-2-inducible T-cell kinase (ITK), blocking T-cell activation, cytokine release, and proliferation.¹
• Belumosudil inhibits Rho-associated kinase 2 (ROCK2) – which is downstream of cytokine and growth factor receptors, and integrins – and inhibits activation of STAT3 and production of IL-21, IL-17, and IFN-γ, which are central in cGvHD pathogenesis.¹
  • In the phase II ROCKstar trial (NCT03640481), belumosudil 200 mg once daily resulted in a best overall response rate (ORR) of 74% in patients with steroid-refractory cGvHD after two or more prior lines of therapy.³
  • The ROCKstar trial included patients with cGvHD refractory to ruxolitinib, addressing a key unmet need: the phase III REACH3 study (NCT03112603) of ruxolitinib indicated ~50% of patients with SR or steroid-dependent cGvHD require alternative therapies (Week 24 ORR, 49.7%).^3,4
• Axatilimab is an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody that depletes monocytes and macrophages, thereby interfering with the activation of fibroblasts, and reducing collagen and extracellular matrix production.¹
  • In the phase II AGAVE-201 study (NCT04710576), axatilimab 0.3 mg/kg every 3 weeks resulted in an ORR of 74% in patients with recurrent or refractory cGvHD after two prior lines of systemic therapy, with responses observed in upper and lower gastrointestinal, esophageal, and lung cGvHD.⁵
• Future directions may focus on identifying optimal combinations of approved therapies and agents with different mechanisms of action, such as extracorporeal photophoresis.

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.