Effects of Axatilimab on Skin in Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (cGVHD) is a common long-term complication of allogeneic stem cell transplantation. It develops when donor immune cells attack the recipient's healthy tissues. The skin is one of the organs most commonly affected. Skin cGVHD can cause inflammation, thickening, hardening, and scarring (fibrosis), which may lead to pain, reduced flexibility, impaired mobility, and decreased quality of life.

Axatilimab is a monoclonal antibody that blocks colony-stimulating factor-1 receptor (CSF1R), a protein found on monocytes and macrophages, which are immune cells involved in inflammation and tissue repair. Axatilimab is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with recurrent or refractory cGVHD after at least two prior lines of systemic therapy. Although clinical trials have shown that axatilimab improves symptoms in many patients, the biological mechanisms by which it reduces inflammation and fibrosis in human tissues are not fully understood.

The purpose of this prospective observational study is to better understand how axatilimab changes immune cells in the skin and blood of people with cGVHD. The study focuses on macrophages because growing evidence suggests that these cells play an important role in promoting tissue fibrosis. Researchers will investigate how macrophages change after treatment with axatilimab and how these changes affect interactions with other cell types, including fibroblasts, which produce connective tissue, and T cells, which regulate immune responses. Understanding these cellular changes may help explain how axatilimab works and identify biological markers associated with treatment response.

This is an observational, non-interventional study. The study does not assign treatment, change a participant's medical care, or determine whether axatilimab is prescribed. Participants who receive axatilimab will do so because their treating physician has independently decided that treatment is appropriate as part of routine clinical care. Researchers will observe biological changes associated with treatment without influencing clinical decisions.

Approximately 15 adults with skin involvement from cGVHD will participate. Ten participants who are planning to start axatilimab as part of their routine care will undergo study evaluations before treatment begins, approximately 2 weeks after starting treatment, and approximately 12 weeks after starting treatment. Five participants with skin cGVHD who are not starting axatilimab will serve as an observational comparison group and will complete one study visit.

Study procedures include collection of small skin punch biopsies and blood samples, review of medical records, and assessment of skin disease. The skin and blood samples will be analyzed using laboratory methods that can examine individual cells and determine where different cell types are located within the skin. These analyses will allow researchers to evaluate changes in immune cell populations, gene activity, and tissue organization before and after treatment. Researchers will also compare these biological changes with clinical measures of skin disease to determine whether early changes in tissue are associated with later clinical improvement.

The primary goal of this study is to characterize the early biological effects of axatilimab on macrophages in the skin. Secondary objectives include evaluating changes in fibroblasts, immune cell organization, and blood biomarkers, and determining whether these biological changes are associated with improvements in skin disease. The study will also compare tissue findings from cGVHD with existing data from systemic sclerosis, another disease characterized by skin fibrosis, to determine whether similar biological pathways are involved.

This study is designed to improve scientific understanding of how axatilimab works in human tissues rather than to evaluate its clinical effectiveness or safety. The knowledge gained may support the development of biomarkers that predict treatment response, improve understanding of cGVHD biology, and guide future research into treatments for cGVHD and other fibrotic diseases.

Inclusion criteria

• Age 18 years or older.
• Diagnosis of chronic graft-versus-host disease (cGVHD) with skin involvement.
• Planned initiation of axatilimab as part of routine clinical care (axatilimab arm) or not planning initiation of axatilimab as part of routine clinical care (control arm).
• Able to undergo a skin biopsy at the time of enrollment.
• Able to provide informed consent.

Exclusion criteria

• Unable to provide informed consent.
• Contraindication to skin biopsy, including severe thrombocytopenia or other conditions that make skin biopsy unsafe in the judgment of the investigator.
• Active uncontrolled infection.