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

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-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients 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 [MSGs], and skin) and the peripheral blood. After 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 after treatment, whereas CD4 Treg cells increased in both the 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 the 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.

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Publication Details

Journal
Blood Advances
Published
2025-05-01
DOI
https://doi.org/10.1182/bloodadvances.2025016170
Citations
4
Primary Topic
Hematopoietic Stem Cell Transplantation
Type
article
Field-Weighted Citation Impact
7.08

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article

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

Nathaniel S. Treister, Kathy Marshall, Frank A. Boksa, Corey S. Cutler et al.
4 citations
Blood Advances
Hematopoietic Stem Cell Transplantation
7.08
article

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

Nathaniel S. Treister, Kathy Marshall, Frank A. Boksa, Corey S. Cutler, Stephanie J. Lee, Amin M. Alousi, Rohtesh S. Mehta, Iskra Pusic, Bruce R. Blazar, Steven Zivko Pavletic, Ana Caroline Costa-da-Silva, Nadarajah Vigneswaran, Sandrine Macé, Jacqueline Wiesehan Mays, Noa G. Holtzman, Olivier Schueller, Ayesha Javaid, Drashty P. Mody, Yu Yao, Rubina Sharma, Beifang Hu, Ran Ji
article en
4 citations

Abstract

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-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients 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 [MSGs], and skin) and the peripheral blood. After 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 after treatment, whereas CD4 Treg cells increased in both the 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 the 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.

Blood AdvancesVol. 9(14)
Brigham and Women's Hospital (US), National Institutes of Health (US), University of Minnesota (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), The University of Texas MD Anderson Cancer Center (US), Washington University in St. Louis (US), Sanofi (France) (FR), National Institute of Dental and Craniofacial Research (US), Fred Hutch Cancer Center (US), Sanofi (United States) (US), Dana-Farber Cancer Institute (US), University of Minnesota Medical Center (US), National Cancer Institute (US), The University of Texas Health Science Center at Houston (US)
Eli Lilly and Company, Sanofi, Celgene, Incyte, National Institutes of Health, University of Texas MD Anderson Cancer Center, Pharmacyclics, National Cancer Institute, National Institute of Dental and Craniofacial Research
Good health and well-being
Openalex Percentile: Top 3%
Hematopoietic Stem Cell Transplantation
7.08
DOIOpen Access PDFOpenAlex
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