New Targets in Refractory Chronic Graft-Versus-Host Disease

Advances in the field of hematopoietic cell transplantation (HCT) research have improved patient outcomes, but transplant complications remain a significant cause of morbidity and mortality, with up to 50% of patients succumbing to relapse, infection, or graft-versus-host disease (GVHD). Even in the current era where the use of post-transplant cyclophosphamide (PT-Cy) has dramatically reduced the rate of acute GVHD, chronic GVHD (cGVHD) remains a major source of morbidity and, eventually, mortality. In a recently published study from the National Marrow Donor Program (NMDP) registry, more than 10,000 transplant recipients were analyzed, revealing rates of moderate to severe cGVHD two years after transplantation still on the order of 10% after PT-Cy with a matched related donor, and 15% with a mismatched donor.¹  In randomized data from the Blood and Marrow Transplant Clinical Trials Network 1703 study published in 2023, where PT-Cy was compared with traditional calcineurin inhibitor (CNI)-based GVHD prophylaxis, cGVHD developed in 21.9% of the PT-Cy-treated patients and 35.1% of the CNI-treated patients.²  Thus, even in the setting of evolving prophylactic strategies, cGVHD remains an important problem for the transplant patient population and a barrier to safe expansion of allogenic HCT approaches.³ 

There have been advances in our understanding of cGVHD pathogenesis in recent years, and thus a number of novel treatment agents are now available clinically (e.g., the JAKSTAT inhibitor ruxolitinib,⁴  the rho-associated coiled-coil-containing protein kinase-2 inhibitor belumosudil,⁵  and the Bruton tyrosine kinase inhibitor ibrutinib).³  Mouse models of cGVHD laid the foundation for these new therapeutic strategies. In the case of this new trial, conducted by Daniel Wolff, MD, and colleagues, the key mouse study identified that colony-stimulating factor 1 (CSF-1)-dependent macrophages were drivers of fibrosis in cGVHD.⁶  This crucial preclinical work was published in 2015 by a team of researchers led by Kelli MacDonald, PhD, and Geoffrey Hill, MD. A subsequent phase I/II trial of CSF-1 receptor blockade administration to target profibrotic macrophages was completed and then published in 2023, with promising results — 58% of the patients reported significant improvement in cGVHD-related symptoms.⁷ 

In this article, describing the AGAVE-201 study (NCT04710576), Dr. Wolff and colleagues present randomized data supporting use of the CSF-1 receptor-targeting antibody axatilimab in patients with recurrent or refractory cGVHD.⁸  A total of 241 patients were enrolled and then randomized to receive one of three doses of axatilimab (0.3 mg/kg or 1 mg/kg every two weeks, or 3 mg/kg every four weeks). The study was performed in 16 countries at 121 unique study sites. The primary endpoint was cGVHD response as measured by the National Institutes of Health consensus criteria after six cycles of therapy. One of the key secondary endpoints was a reduction in symptoms, as measured by the 28-item Lee Symptom Scale (LSS). Overall response rates were high with all three dosing strategies, with rates of 74% (95% CI 63-83) in the 0.3 mg/kg arm, 67% (95% CI 55-77) in the 1 mg/kg arm, and 50% (95% CI 39-61) in the 3 mg/kg group (who, of note, were treated every four weeks rather than every two weeks). Responses were rapid, with a median time to response of two months. Intriguingly, a decrease in steroid use and even some discontinuation was reported in patients who were steroid dependent at the time of axatilimab commencement. Symptom scores were also improved in all three dose arms (as measured by a greater-than-five-point reduction on the LSS).

Less than 10 years after the initial discovery that CSF-1-dependent macrophages played a key role in cGVHD biology in mice, we have mature data from a randomized trial demonstrating that targeting this population with a monoclonal antibody can benefit patients. This is a remarkable example of the power of translational research. We now have one more strategy to improve outcomes and reduce the symptom burden in patients with cGVHD.