A Novel Approach to Chronic GVHD With Axatilimab: Dr Daniel Wolff

Daniel Wolff, MD, PhD | Image Credit: © University Hospital Regensburg, Germany

In August, the FDA approved axatilimab (Niktimvo; Incyte) to treat chronic graft-versus-host disease (GVHD) in patients who have progressed on at least 2 prior systemic therapies.¹ The drug is a colony stimulating factor (CSF)-1 receptor inhibitor, which is a new target to treat chronic GVHD.

In an interview with The American Journal of Managed Care^® (AJMC^®), Daniel Wolff, MD, PhD, professor at University Hospital Regensburg in Regensburg, Germany, an investigator on the AGAVE-201 trial,² which was used to support the approval, explained the superior response rate of axatilimab in patients who are heavily pretreated, as well as the new side effect profile to consider with this new mechanism, and future research into axatilimab.

This transcript has been slightly edited for clarity.

AJMC: What does the approval of axatilimab add for patients as a new treatment for chronic GVHD?

Wolff: Axatilimab targeting the CSF-1 receptor is a totally new agent in the field, which acts in a way that it acts on a target not thought about before and not targeted before. Classical immune suppression is oriented toward T cells and B cells, so the adaptive immune system.

Now with the CSF-1 receptor–targeting treatment being axatilimab, you target monocytes and macrophages, which are not targeted by other treatments. So, you have an option for patients failing other treatment options, and one that results in high response rate. Even patients failing a median of 4 lines had a response rate above 50%, and with the lowest dose, even 74% had a benefit, which was lasting for most of the patients.

So, in summary, we have a new treatment option, which is totally different from the others and results in high response rates, even in patients who are heavily pretreated.

AJMC: Since axatilimab has a new target compared with other GVHD treatments, what do providers and patients need to know about new or different potential adverse events?

Wolff: Since the mechanism of action is totally different compared with other agents, the side effect profile is also different from other agents. There is one very well-known side effect, which is actually not a side effect but can cause diagnostic dilemma. Because you deplete Kupffer cells with axatilimab, you increased the half time of circulating liver enzymes and pancreatic enzymes. That is not organ damage, but it decreases your ability to diagnose organ damage caused by other things. That's a known side effect from CSF-1 receptor blockade. Periorbital swelling is a frequent side effect, which rarely occurs on the low dose, but if you increase the dose of axatilimab, which is not in the approval label, then this is a big issue.

Looking at infectious complications on axatilimab, for the low dose, it didn't appear to be an issue. Patients had no more infection than this population usually had. There were patients placed on the trial with ongoing active infections and there was no safety signal on that side. So, in general, yes, there are some side effects. There can be also infusion side effects very rarely, but it happens, but compared with other treatment options like calcineurin inhibitors it's pretty well tolerated.

There is one side effect, which actually is not a side effect but has to be thought about. It's an infusion, so you have to show up every 2 to 4 weeks at your physician to get the infusion. It's not a pill.

AJMC: Last year around the American Society of Hematology annual meeting, where data on axatilimab were presented, you mentioned that future trials of axatilimab will focus on primary treatment of GVHD.³ Are there any updates on this research and what will be the benefit if axatilimab can target earlier disease?

Wolff: There are now 3 trials planned or going to start. One that's the most exciting trial is evaluating frontline treatment without steroids. Steroids have been the standard of care for the last 40 years treating chronic GVHD, and everyone knows the side effects of steroids. This trial will now evaluate axatilimab in combination with ruxolitinib with a steroid-free approach of frontline treatment of chronic GVHD. We're very excited to see the results, which we will probably get into the next 2 years. This trial is just starting right now.

There will be another frontline treatment trial evaluating axatilimab in combination with steroids vs steroids alone, which will start probably around January next year. This is comparing the standard approach vs the standard approach plus axatilimab. There will be a third trial in Europe repeating the AGAVE-201 trial in advanced chronic GVHD, but now randomizing the optimal dose vs best available treatment. Those are the 3 trials, which are planned and will start soon or are just starting.

Why go to first-line treatment? The AGAVE-201 trial focused on patients with advanced GVHD who already had nonreversible damage in their affected organs. Preventing that damage from occuring would make a whole lot of sense. The other aspect is the mechanism of action targeting the CSF-1 receptor pathway without increasing significantly infectious risk makes it very attractive for early forms of treatment, because you can go with a combination treatment targeting several effectors in chronic GVHD without having the risk of overimmune suppression. That that's the theory. Whether that turns into success has to be shown in the clinical trial. That's why we perform those clinical trials.

References

1. Santoro C. FDA approves axatilimab for chronic graft-vs-host disease. AJMC. August 15, 2024. Accessed October 18, 2024. https://www.ajmc.com/view/fda-approves-axatilimab-csfr-for-chronic-graft-vs-host-disease

2. Wolff D, Cutler C, Lee SJ, et al; AGAVE-201 investigators. Axatilimab in recurrent or refractory chronic graft-versus-host disease. N Engl J Med. 2024;391(11):1002-1014. doi:10.1056/NEJMoa2401537

3. Caffrey M. Understanding AGAVE-201 and unmet need in chronic GVHD. Am J Manag Care. 2024;30(1):SP62.