Advances in the Management of Graft Versus Host Disease - Episode 11

Treatment Selection for Steroid-Refractory GVHD

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Hannah Choe, MD, leads the discussion on clinical experiences using off-label regimens to treat steroid-refractory chronic GVHD, and the optimal sequencing of therapy.

Yi-Bin Chen, MD: We have 3 new toys to play with in chronic graft-vs-host disease [GVHD]. Hannah, what other agents or modalities do you use to treat people with steroid-refractory chronic GVHD?

Hannah Choe, MD: Things are changing. In the last 6 months, the landscape has opened up for chronic graft-vs-host disease. But what we’ve historically used as an alternative at our institution, particularly with sclerodermatitis, is ECP [extracorporeal photopheresis]. ECP has a lot of historical data but not a ton of great evidence in terms of large clinical trials. It’s something that we’ve consistently seen benefit our patients given enough time.

Other agents that have been tried are rituximab, sirolimus, and mycophenolate. Unfortunately, as you could read into REACH3 or the belumosudil trial, they have only so much response rate, which is inferior to ruxolitinib and belumosudil. The duration of response is very limited. We’ve been excited about the fact that we have ruxolitinib and belumosudil as options for patients. They have decently durable responses and give patients an improvement of the quality of life.

Yi-Bin Chen, MD: It will be interesting to see how we sequence these. With real-world experience, it will be interesting to see combination therapy with these new drugs. We’re already talking to our colleagues around the country and companies whose ideas are already being tossed around to use these therapies in an earlier line or for specific phenotypes. Hopefully these trials get underway. We can collaborate and make progress and learn how to use these drugs. But we can be happy that this progress has been made.

Hannah Choe, MD: The fact that belumosudil has such a great response rate, even in patients who have failed ruxolitinib prior, is really encouraging. Sometimes what we expect after a failure therapy is that they’re going to have a lower response rate to next line. In this case, we can give ruxolitinib first. We have more experience with it because it’s been used off-label for much longer. Then we can transition to belumosudil in case of failure or intolerance. We can still potentially get another year of response with belumosudil with a response rate of 68%. It’s nice to have that in our armamentarium for these patients.

Yi-Bin Chen, MD: I totally agree. We’ll get back to the sequencing in a second. To illustrate how more work is needed, if you look at all these trials, they have overall response rates of 50% to 70%, but the minority of them are CRs [complete responses]. Sophie, this gets back to what you were saying: by the time you’re doing second-line therapy, it’s too late, and there’s a level of irreversible organ damage. Maybe these new drugs change how much is reversible and how much isn’t, but it may be too late. Looking at them, you have single-digit CR ranges, and that’s sobering. But you’re right. If I have patients on steroids and need to do therapy, I add ruxolitinib. This is off-trial. My instinct is if ruxolitinib doesn’t work or hits a plateau in response, then I’d add belumosudil. That’s my sequence right now.

Hannah, you brought up ECP. ECP is an effective therapy for many patients, as all of us who prescribe it know. It’s also a big investment of resources for the patient in the center, so all those logistics play in. Oftentimes, that practicality dictates the sequence of these therapies. What’s the sequence of therapy like at Duke Health?

Nelson J. Chao, MD, MBA: We probably space it very similarly. We use steroids first and then ruxolitinib. For skin, we primarily use ECP. It really helps the patient. The other part that ECP helps is that they’re back in your center. If they’re not eating well or if they have an infection, you’re seeing them twice a week. One of the problems and downsides of chronic graft-vs-host disease is that they’re no longer in the medical center; they’re back in the community. All of us had patients come back 6 months later with horrible chronic graft-vs-host disease because it was never picked up and nobody thought about it. Some of the better outcomes with ECP are because they’re close and you’re monitoring them closely.

Yi-Bin Chen, MD: Interesting. Is the sequence different at Ohio State University Comprehensive Cancer Center?

Hannah Choe, MD: It’s variable. It’s similar, with ruxolitinib after corticosteroids and then, as always, clinical trial. More recently, with the FDA approval of belumosudil, we’re putting belumosudil before ECP. To the point that you just made, logistically it’s very taxing for the patient to come so frequently, especially if they’re working and back to their regular life otherwise. We follow a similar pattern.

The only caveat I’d add is that it’s all dependent on the toxicities. Ruxolitinib and belumosudil are very well tolerated, as Nelson was saying, but the cytopenias with ruxolitinib can be difficult. Interestingly, we don’t see that with belumosudil, so that would be the reroute, which would be to do belumosudil first instead of ruxolitinib in those patients for whom you have more concerns regarding cytopenias. But we don’t have phase 3 data with belumosudil to know how it compares with best-available therapy or even ruxolitinib in terms of tolerability. As Nelson mentioned, it seems like it’s well tolerated. For those reasons, ruxolitinib, then belumosudil, and then ECP is what we’ve been following more recently.

Yi-Bin Chen, MD: How about at the Medical University of South Carolina?

Sophie Paczesny, MD, PhD: Exactly the same approach. Will they do a phase 3? It has been bought by Sanofi, so they’re planning on a phase 3.

Hannah Choe, MD: If I were them, I would.

Yi-Bin Chen, MD: Maybe. Comparing the agents would help us understand. It takes a lot of collaboration. We have these new therapies and we’re using them actively, but we also have no idea how to discontinue them. There’s some fear with ruxolitinib that if you stop it too quickly, there’s a surge of inflammation or cytokines. We have a report of a few patients with some inflammatory lung syndromes after doing that. Not only do we not know how long we use these agents for—it’s usually guided by how our patients are doing—but when we transition, we also don’t know whether to stop or decrease. If we’re tapering, we don’t know how long to taper. Hopefully all this real-world experience will shed some more light on it.

Transcript Edited for Clarity