Chronic graft-versus-host disease (cGVHD) affects 30-50% of all allogeneic hematopoietic graft recipients with few good treatment options. Corticosteroids are the standard first-line treatment, but fewer than 20% of patients experience even a partial response to this approach.

“Many patients will require years of treatment,” said Carrie Kitko, MD, associate professor of pediatrics, Ingram professorship in pediatric oncology and medical director of the Pediatric Stem Cell Transplantation Program, Vanderbilt University Medical Center, who moderated the Feb. 13 session Concurrent: Cytokines and Fibrosis in Chronic GVHD.

More treatment options are on the way. The U.S. Food and Drug Administration (FDA) has approved three new drugs to treat cGVHD: ruxolitinib, belumosudil, and axatilimab. Research continues into new agents, the potential to repurpose existing antifibrotic agents, and novel biomarkers to guide targeted therapy.

Ruxolitinib reduces collagen deposition in the lungs, improving lung function. It may have a tissue-level response to reduce fibrosis or slow fibrosis formation. A trial in bronchiolitis obliterans syndrome (BOS) showed significant improvement in lung function, particularly in patients who had been diagnosed within the previous six months. The median time to National Institutes of Health (NIH) response criteria was 7.7 months.

Belumosudil is a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor and improves production of regulatory T cells (Tregs) to reduce chronic inflammation and organ fibrosis. The drug is particularly active in the joints/fascia, skin, and lungs.

Axatilimab targets colony-stimulating factor-1 (CSF-1) receptor-dependent monocytes and macrophages to reduce inflammation and fibrosis. Organs responded quickly by patient and clinician assessment but more slowly by NIH assessment. And response increases over time for at least 180 days.

“These drugs work in these fibrotic diseases, but you need to give them time,” Kitko said.

Time is something patients with BOS don’t have. BOS affects up to 15% of all allotransplants, and five-year survival is 40% at best. One reason for this is late diagnosis. The NIH criteria lack sufficient sensitivity to detect BOS early.

“We know that BOS is progressive,” said Joe Hsu, MD, MPH, assistant professor of pulmonary, allergy and critical care medicine and director of the Stanford Lung GVHD Clinic, Stanford University Medical Center. “You have progressive airflow obstruction until the end of life.”

The pathophysiology of BOS can inform treatment. If progressive obstruction leads to organ failure, why not use anti-fibrotics to slow or reverse fibrosis? The two FDA-approved anti-fibrotics, pirfenidone and nintedanib, are not immune suppressive and act on the final common pathway to organ dysfunction seen in cGVHD.

The Safety and Tolerability of Pirfenidone for Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplant (STOP-BOS) trial and a four-year extension found that pirfenidone stabilized percent predicted forced expiratory volume (ppFEV1)_. A subset of responders had a significant response with improvement in liver, skin, eyes, mouth, and physical function as well as the targeted pulmonary function.

The next pathophysiological target is transforming growth factor beta (TGFβ), a key pathway in fibrogenesis. A novel Shc inhibitor can reduce airway fibrosis as well as collagen precursors and formation in a mouse model. The agent also reduced collagen and fibrosis in murine airway transplantation.

“The promise of BOS is still undefined, and anti-fibrotics represent a novel therapeutic target. More research is necessary,” Hsu said.

Macrophages are another understudied therapeutic target to reduce or reverse fibrosis. In cGVHD, aberrant B cells can nudge monocytes and macrophages to alternative activation into tissue-resident M2 macrophages that induce profibrotic cytokines that promote fibroblast formation and tissue fibrosis.

“Tissue macrophages are the final common pathway immune cell of fibrosis,” said Julie Boiko, MD, PhD, research associate in translational science and therapeutics, Fred Hutchinson Cancer Center, and acting instructor, Division of Pediatric Hematology/Oncology, University of Washington, Seattle Children’s Hospital.

Macrophages induce CSF-1, interleukin-17 (IL-17), and TGFβ, Boiko continued. All three have physiologic roles that are dysregulated in cGVHD. That suggests cGVHD therapy can be tailored for specific cytokine-driven perturbations.

In mouse models, CSF-1 receptor blockade prevents morbid, fibrotic GVHD and the pharmacologic inhibition of IL-17 mitigates experimental cGVHD.

TGFβ is fibrosis’ bridge between immune cells and non-immune cells, Boiko said, making it a particularly attractive target. It also accounts for the activity of pirfenidone to reduce macrophage infiltration, TGFβ, and collagen deposition in a murine BOS model.

“We are really excited about these life-changing cGVHD drugs, but challenges remain,” she added. “Immunologic pathway specific agents work well for some, but not all, patients.”

The aim is to identify specific, causative aberrant immune pathways in individual patients prior to irreversible cGVHD organ damage.

Early work with peripheral blood assays identified pathway-specific gene expression signatures in a GVHD mouse model. Those same signatures can be seen in cGVHD patients. Gene signatures from peripheral blood samples may eventually be used to identify individuals with IL-17 and CSF-1-dysregulated cGVHD.

This and other sessions at the 2025 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT® and CIBMTR® will be available for on-demand viewing for registered attendees following the live presentation.