I still remember her eyes — the sorrow captured in them, the pleading for reprieve, for relief. Of course, I also cannot forget her skin, diffusely thickened and red from chronic graft-versus-host disease (cGVHD). So many months she had to endure the comings and goings, to and from the hospital, dealing with the morbidity of her immune system at war with itself. I met her when I was a medical student, trying to sort through what I would become. It was she who led me to the field of stem cell transplantation. This was many years ago, but what I gathered was that she needed more than what we were able to offer her then.
During yesterday’s Plenary Scientific Session Safety and Efficacy of Axatilimab at 3 Different Doses in Patients with Chronic Graft-Versus-Host Disease (AGAVE-201), Daniel Wolff, MD, PhD, professor of medicine and chair of the multidisciplinary GVHD Center at the University Hospital Regensburg, shared encouraging results from an arduous effort to help provide what that patient required: a proposed solution to her cGVHD, and perhaps finally, a step towards healing. Will axatilimab be the catalyst to giving cGVHD the “ax” for good? To understand the magnitude of Dr. Wolff’s presentation and the pertinent outcomes of this pivotal phase II trial, let us revisit the complexities of cGVHD.
The complete pathophysiology of cGVHD remained unknown for many years despite ongoing advancements in stem cell transplantation. This was due, perhaps, to the multiorgan and heterogenous nature of insult or to the fact that there are several mechanisms involved that can result in profound morbidity or resultant mortality. Thanks to meticulous and relentless efforts over several decades, our understanding of the biologic drivers of cGVHD has expanded, and standardized methods for evaluating and reporting on clinical cGVHD have been developed, leading to three drug approvals for cGVHD. However, despite these therapeutic options, treatment refractoriness remains a significant concern, particularly in those with severe sclerotic and fibrotic manifestations of cGVHD.
The complex mechanisms underlying cGVHD occur across several phases, with tissue injury resulting in early inflammation, T-cell and B-cell dysregulation leading to chronic inflammation, and ultimately fibrosis. Fibrosis results from abnormal tissue repair driven by activated macrophages dependent on colony-stimulating factor (CSF-1), triggering fibroblasts and clinically manifesting as bronchiolitis obliterans or severe sclerotic cGVHD. After researchers had elucidated the pathophysiology of cGVHD, CSF-1 receptor (CSF-1R)-dependent macrophages were recognized as a potential therapeutic target. With an “ax” to grind, and thanks to the preclinical work of Kelli MacDonald, PhD, Bruce Blazar, MD, Geoffrey Hill, MD, and others, axatilimab entered the scene. Axatilimab, an anti-CSF-1R monoclonal antibody, targets the activated macrophages involved in the fibrotic phase of cGVHD. With axatilimab’s unique mechanism of action and proven biologic and clinical activity based on results from an initial phase Ib/II trial, this phase II trial was pursued to determine the safest and most effective dose of axatilimab.
Stefanie Sarantopoulos, MD, PhD, an expert in GVHD whose laboratory at Duke University School of Medicine focuses on understanding the immunopathologic mechanisms of cGVHD, introduced the plenary session. As she passed the baton to Dr. Wolff to cover the important results of the AGAVE-201 trial, I thought of the patient I met so many years ago and the many since. I slowly breathed out the breath I did not know I was holding as I remembered them, listening intently as Dr. Wolff began his coverage of the randomized, global, multicenter trial design. Adult and pediatric patients with recurrent or refractory active cGVHD whose disease had progressed after two prior therapies were randomized in a 1:1:1 fashion to one of three treatment groups with a distinct dose of intravenous axatilimab provided (0.3 mg/kg every two weeks (Q2W), 1 mg/kg Q2W, or 3 mg/kg every four weeks). The overall response rate (ORR) by cycle 7, defined based on NIH 2014 consensus criteria, was the primary efficacy endpoint, with frequency and severity of treatment-related and treatment-emergent adverse events serving as safety endpoints.
With 241 patients enrolled, there were 239 patients treated by data cutoff in April 2023. Despite a heavily pre-treated population with a median of four lines of prior therapy, all three cohorts met the primary endpoint. Most notably and quite surprisingly, the lowest dose cohort had the best ORR at 74%, with 60% of these patients still responding at one year. Dr. Wolff also reported that axatilimab was generally well tolerated.
Dr. Wolff reflected that these encouraging results and new therapeutic direction have the potential “to fundamentally change the course of this devastating disease.” He credited the outstanding partnership and commitment of Syndax for driving the development of axatilimab from a novel concept to perhaps a critical weapon in the therapeutic armamentarium for cGVHD. The next step in finally giving the “ax” to cGVHD will involve moving axatilimab to the frontline setting for patients with newly diagnosed cGVHD.
Dr. Ragon indicated no relevant conflicts of interest.