Selecting cGVHD Treatments Based on Organ Involvement

The management of steroid-refractory chronic graft-vs-host disease (cGVHD) has been expanded by several FDA-approved treatment options. Hannah Choe, MD, an associate professor of Internal Medicine in the Division of Hematology at The Ohio State University, considered preferred steroid-refractory cGVHD treatments with fellow oncologists participating in a virtual Case-Based Roundtable event. The conversation also explored the use of newer agents like axatilimab (Niktimvo), considering their organ-specific efficacy, safety profiles, and practical administration logistics.

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DISCUSSION QUESTION

Considering available clinical trial data, what would be your preferred therapy for a patient with steroid-resistant cGVHD?

Bramham Reddy, MD: I thought ruxolitinib [Jakafi] would be the first but when collaborating and discussing with the transplant team, [it depends].

Hannah Choe, MD: So you see ruxolitinib a lot.

Inna Shmerlin, MD: I think ruxolitinib is probably one of the better options that we have. For those of us who are not transplanters, we’re comfortable with ruxolitinib because we’ve used it in myelofibrosis…. That would probably be my go-to.

DISCUSSION QUESTIONS

• What are the key factors that drive your decision making for treatment?
• Does a specific organ involvement such as lung, gastrointestinal (GI) tract, or genitourinary (GU) tract change your treatment approach?

Choe: Remember that our options for FDA-approved therapies, besides steroids, are ruxolitinib, ibrutinib [Imbruvica], belumosudil [Rezurock], and axatilimab. But historically, chronic GVHD has been treated with a whole host of different immunosuppressive therapies. So it could be a very wide range, and so I’m interested to know why you would choose ruxolitinib, or if there’s a specific organ that would make you choose a different option.

Andrew P. Dalovisio, MD: I think ruxolitinib is good because it’s shown efficacy across organ systems, and also there’s a lot of comfort with it and good longer-term data.

Choe: Not ibrutinib as much, but belumosudil and axatilimab also have efficacy across the different organ systems as well. The approach might be a little bit different, because belumosudil is oral and axatilimab is intravenous. There are a bit more data with lung involvement with belumosudil that drives some transplant physicians to use belumosudil for patients who have lung involvement or bronchioles obliterans. Same thing for axatilimab, that there’s maybe more efficacy for the lung, in particular, especially because of the mechanism of action of axatilimab being different and hypothetically better for more sclerotic manifestations. Then the GI tract or GU tract, maybe, depending on the type of inflammation, might drive someone’s use.

The other thing is to consider is the adverse event profiles of these medications that might drive your decision making. If you have cytopenias, maybe ruxolitinib is not the best option, because you don’t have the cytopenias with belumosudil, but if the patient has a pre-existing history of headaches, then maybe you’re going to want to avoid belumosudil because they have higher risk of having headaches, etc. Knowing the adverse event profiles of these drugs can certainly drive which option you might use at this point. Whether you want to use an oral vs an IV medication might also affect your decision.

DISCUSSION QUESTIONS

What do you think of the data from the AGAVE-201 trial (NCT04710576)?¹

Choe: Would the axatilimab data change your current practice? Do you anticipate seeing it more often? How would you employ it?

Tejo N. Musunuru, MD: It definitely sounds promising in patients with GI GVHD more than others, whether it’s esophageal, upper, or lower GI. I would say having more treatments is always a good thing, but it also comes down to the choice of the medication. We probably have to pick and choose at this point. The data are very impressive for the GI GVHD, and not so much for skin. There was 9% complete response rate for the skin. That’s what I would probably try to do. I haven’t used this medication before, or tried to get it approved, but I would say having other options is always a good thing.

Would you ever think that these would be compared against each other, to see which one may be better than the other one?

Choe: Not directly.... There’s a study looking at the combination of ruxolitinib and axatilimab up front, and that’s currently enrolling [NCT06388564]. What that’s going to compare is the combination vs ruxolitinib alone vs steroids. You would be able to at least compare that combination to ruxolitinib alone, so that might give you an idea of how much the axatilimab is adding in the upfront setting. That’s not in this setting, which is steroid-resistant or steroid-refractory cGVHD.

These studies were done in very refractory patients, so patients on AGAVE-201, who got axatilimab had [disease progression] on ruxolitinib...before they went on to axatilimab. When you see the responses that are still 25% in the skin, even though that does seem like a low number, these are patients [with disease progression after] all the other lines of therapy and still had a quarter with a higher response now with axatilimab. For someone who treats GVHD, it’s very encouraging, because in an area where I have nothing to offer my patients, at least a quarter of them have some response to this new therapy—huge game changer.

The other consideration is that now, when we use it, we’re not necessarily waiting for the 2 years for patients to have cGHVD before we start it. The hope is if we start earlier, are we going to get better responses? Are we going to have longer duration of response? Are we going to be able to reverse scar tissue formation in some of these patients, etc?

In my center, we start the patient on it, and then we transfer the patient to the rural infusion center to continue to receive it. It is also similarly very well tolerated, where you have very few adverse events, especially at that 0.3 mg/kg every-2-week dose. You do see some liver enzyme changes, and that’s because it’s anti-CSF1R [therapy], and this is also on cells in your liver, so you will see an aspartate transaminase or alanine transaminase elevation...that comes with the axatilimab, but it is not related to liver toxicity. It’s more just a laboratory change that does tend to improve with holding it or reducing the dose. So generally, if that happens, depending on the severity of it, I continue or hold and then resume once the once the transaminase elevation passes.

Mark Charbonnet, MD: That would help us out a lot in the community, when you give the first dose, and we just continue every 2 weeks thereafter, because then the [insurance] approval process has already happened and we’re continuing the therapy from the transplant center, and it’s a lot easier to have a continuation therapy approved than for us in the rural area trying to get a newer label drug that looks very effective, but they will ask “Have you used it before?” So that’s great if you do the first dose.

Choe: For patients getting it at the local centers, I have occasionally run into them not getting it covered, and unfortunately, seen patients have progression of their cGVHD as they come off of it. That has been challenging as well. But that might continue to be the norm, to start it, to see that response, and then transfer this patient back to their local center. It’s difficult because it is an every-2-week drug and so patients have to drive back in 2 weeks. Sometimes they’re driving 5 or 6 hours to come see us. I’m based in Columbus, Ohio, so [they are] driving from all over...to come see us to get started. We are very excited to be able to get them treatment locally when possible. Because it is very well tolerated, we’re able to transition it pretty easily.

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DISCLOSURES: Choe previously reported relationships with Incyte Corporation, Sanofi, Ironwood Pharmaceuticals, AbbVie, Actinium Pharmaceuticals, Inc., and Regimmune.

REFERENCE

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