Belumosudil reduces oral chronic graft-versus-host disease tissue inflammation and fibrosis: a ROCKstar companion study

• Belumosudil treatment for cGVHD decreased collagen content in the oral mucosa.

• Belumosudil reduced IL-17 production and inflammation in the oral mucosa and minor salivary glands in oral cGVHD.

Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin (IL)-17 activity and promotes regulatory T-cell (Treg) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 subjects with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSG], and skin) and peripheral blood. Following belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non-T cells in the oral tissues. Immune cell frequencies in the OM decreased following treatment, while CD4 Tregs increased in both MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in OM. Additionally, salivary transforming growth factor β1 (TGF)-β1, a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. The ROCKstar study was registered at www.clinicaltrials.gov as NCT03640481.