The Changing Landscape of Chronic Graft vs. Host Disease - Episode 6

Third-Line Treatment Approaches for Acute GVHD

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John DiPersio, MD, PhD, and Michael Bishop, MD, discuss third-line treatment options for patients with acute and steroid-refractory GVHD.

John DiPersio, MD, PhD:In the acute GVHD [graft-vs-host disease] setting, after you have someone who’s been having ongoing diarrhea on a JAK inhibitor, and they’re not, this is acute. What are your third-line approaches to those patients?

Michael Bishop, MD: At our own institution [the University of Chicago], we like extracorporeal photopheresis. The reason I like that is because it’s not a direct drug intervention because there are already a number of agents. The agents we’d be looking to add would potentially be an anticytokine monoclonal antibody. We have looked potentially at another kinase inhibitor, like in ibrutinib. We always try to get on a clinical trial of course, right?

Usually, the clinical trials are available if they have to be. They’ve had only frontline therapy with steroids. But we tend to use a lot of ruxolitinib in that setting.

I like extracorporeal photopheresis because of lack of drug interaction. We can have responsiveness, and we’ll continue the ruxolitinib through that with the idea hopefully that we’re going to get steroid sparing and get the disease under control. Whether that’s correct biologically, I don’t know. But the only problem with extracorporeal photopheresis is that I get a lot of pushback from patients having to come in twice a week for those first 4 to 8 weeks trying to get it in. You know that’s the last thing they want to do. As a matter of fact, they’ll scream and bite before they do it. But that’s generally our approach.

John DiPersio, MD, PhD: Yes, it’s a major commitment on the part of patients. I don’t know if everyone understands how expensive photopheresis is. Most of us have not seen any hospital bills, but the cost of a year of photopheresis twice a week every other week is around $350,000 to $400,000. That’s quite substantial when you think about Medicare paying transplant centers only around $70,000 for an allogeneic stem cell transplant.

This can be very expensive, and it’s also tough on the patients, right? They get wiped out and they must travel sometimes long distances to get their collections. When they’re outpatients, they need to stay overnight and get it 2 days in a row and then come back in a couple of weeks. How we do photopheresis in the defined best of care with this approach has not been worked out very well.

And also, how it works. We don’t even know how it works. There are lots of theories, so we’re giving a treatment that’s phenomenally difficult and expensive, and we’re not really sure how it works. It’s frustrating for us as physicians to be in the middle of a treatment that’s complicated and expensive, and when we don’t know the mechanism by which it might affect patients.

I also wanted to echo your comments about clinical trials. For anybody who has steroid-refractory graft-vs- host disease, there’s a drug that’s approved, Jakafi. It’s perfectly appropriately to treat any patient who has steroid-refractory GVHD with that FDA-approved drug, and it’s effective as based on the phase 2 studies and the randomized phase 3, REACH2 study.

The other drugs out there that we might use, including photopheresis, would be primarily for those severely progressing patients in the hospital. We might consider, in addition its clinical trials, we have used quite a bit of vedolizumab as an inhibitor of alpha-4 beta-7, which is the integrin that’s key for trafficking of T cells to the GI [gastrointestinal] tract. It’s approved for the treatment of patients with IBD [inflammatory bowel disease]. And it may help some patients with that particularly aggressive GI graft-vs-host disease.

What we found and what others have found is that sometimes, if you treat that with vedolizumab, people get worsening skin graft-vs-host disease ironically, which is interesting. So far, the randomized trials of vedolizumab have not shown a particular differential benefit of this drug over standard of care. As far as what’s out there, there are some interesting trials looking at antibodies to specific T-cell markers.

There’s a ricin conjugated CD3/CD7 combination that was effective but caused a lot of problems. It was put on hold, and it’s about ready to be restarted through the CTN [Clinical Trials Network]. It’s called T-Guard, which has been used in these very severe cases. We get back to the issue of whether it’s better to try to wait for people to get this severe GVHD or try to intervene early with some more targeted therapies, so you don’t let the disease get so progressive.

Transcript Edited for Clarity