Treatment Options: Steroid-Refractory GvHD


Experts define and review treatment options for patients with chronic GvHD that are also steroid refractory.


Hannah K. Choe, MD: To add to the diversity of how we approach chronic GVHD, there are a lot more institutional bias and standardized differences in approaches than for acute. For example, restarting calcineurin inhibition or sirolimus, you may not [even do it] depending on the time it has been since the discontinuation of it, I will oftentimes resume it. It also depends on the severity of the chronic GVHD so that I can potentially just resume that without actually giving steroids, if it’s a very mild chronic GVHD and it’s very soon after the discontinuation, or taper, of it.

Corey Cutler, MD, MPH, FRCPC: Let’s move into the steroid refractory setting. [Doris M Ponce, MD] gave us a broad overview of the 3 compounds that we now have approved in the second-line setting. We have both ibrutinib and ruxolitinib. Ibrutinib, as Doris mentioned, is based on an open-label phase 2 trial in a very selected, perhaps earlier-stage, chronic GVHD patient group. Then, in the ruxolitinib trial, which was larger and randomized, compared against a best available care scenario, which is what we actually do in clinical practice. With 2 drugs approved in the second-line setting, how do you choose between one and the other?

Hannah K. Choe, MD: We also have belumosudil, correct?

Corey Cutler, MD, MPH, FRCPC: That is in the third line.

Hannah K. Choe, MD: Interesting. We do not use ibrutinib at OSU [Ohio State University] because of toxicity and tolerability, and because we don’t have great data to support it, as you mentioned. The phase 1b/2 trial was a combination study with phase 1b, not just a phase 2 study, and it’s only with 42 patients and almost three-quarters of patients had treatment-emergent adverse events. We see that in practice, that patients are not able to tolerate it. As we were mentioning before, that we have more fragile patients bleeding and, thus, bruising… we do not use it, even though it is FDA approved. We do directly go to ruxolitinib after steroids for refractory chronic GVHD, if a trial is not an option.

Corey Cutler, MD, MPH, FRCPC: Yi-Bin, what is your approach?

Yi-Bin Chen, MD: Very similar. I wouldn’t say that we don’t use ibrutinib at all, but it’s very rare. We’ve used ruxolitinib for second line in chronic graft-vs-host disease for several years partly because we felt it was the best option and many patients do benefit from it one way or the other, be it in terms of actual overall response, the ability to taper steroids, or other metrics such as that. Our experience with ibrutinib is what Hannah describes, and Corey, you [and colleagues] published a real-world experience, right? What did that show?

Corey Cutler, MD, MPH, FRCPC: So, we did. We looked at all of the patients who were given commercial prescriptions for ibrutinib after the FDA approval. It was a number just greater than 50 patients who were given ibrutinib. The median time to failure on ibrutinib, and failure here was defined as starting a new agent for chronic GVHD relapse, or death, which was only 4 months. Predominantly, 95% of failures were related to starting a new compound. That tells us that physicians are trying ibrutinib by giving it a 3- or 4-month attempt and then moving on when they’re not seeing adequate responses. In my personal practice, I similarly reach for ruxolitinib almost all of the time. Patients who have B-cell malignancies, or patients who have deep cytopenias when I’m going to treat with chronic GVHD, are the patients [for whom] I will often consider using ibrutinib instead of ruxolitinib. But then, we have the third agent that’s approved in this scenario, belumosudil. It’s a compound that I was fortunate enough to be heavily involved with in the development. We ran 2 studies. First, the dose-escalation trial and then a randomized phase 2 trial, and the response rate was about 75% in a very heavily pretreated patient group. Right now, I use a lot of belumosudil. It is tricky to determine what constitutes a line of therapy, whether steroids plus sirolimus constitutes as one line, or two lines, but many of us are reaching for belumosudil earlier and earlier. I don’t think we have any evidence that it’s better or worse than ruxolitinib. It would be great to determine which patients would benefit from one or the other. How are we going to do that, Yi-Bin?

Yi-Bin Chen, MD: I don’t know. That’s a big challenge for us. We have these options, and we’re going to move them up in the further lines of therapies. We’ll probably get more options for treatment and access to these agents. There’s a big call to develop some biomarkers. Although we throw this term around, a biomarker of response can help predict for us, in some way, which patient will respond to which therapy, most likely. You look at the clinical trial results of all of these agents and the overall response rate somewhere between 50% to 75% depending on what trial you look at, with the vast majority of these responses being partial responses. It would be great to try to match the drug to the patient. I can’t believe it’s going to be clinical phenotype, I think it’s going to be some biological metric or biological biomarker, if you will.

But, what we do know from the experience right now, Corey, is that all of us are using these drugs in combination. We all feel comfortable about this, and we should share that. In the trial experience, it was always the case that you have to stop one drug to go on the trial to get access to the next agent. But in practice, the motivation to start a next line of therapy is not always because your previous line is failing, right? A lot of our motivation is that the previous line worked, but it just hasn’t worked good enough. That’s a discussion that you have with your patient. You’ve achieved the PR [partial response], but that PR’s just not good enough for their overall quality of life, or anything else. You want to add on something else to augment that response and make it better, or so then you feel comfortable about being able to get off of the steroids completely. That’s the majority of our motivations these days for adding something on top of ruxolitinib. We add belumosudil, photopheresis, or something. It’s a discussion with the patient, or a trial to try to improve upon that response.

Corey Cutler, MD, MPH, FRCPC: No, I agree completely. Most of us feel uncomfortable stopping a drug that did have some benefit and we’re worried about seeing a flare of disease as you wait for the novel agents to kick in, which can take 2 [months or longer] when, in particular, we’re dealing with sclerosis.

Transcript edited for clarity.

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