Treatment Options for Chronic GvHD


Comprehensive discussion into the available treatment options for patients that present with chronic GvHD.


Corey Cutler, MD, MPH, FRCPC: As we talk about therapy and responses, we’re going to limit our discussions to what we would call moderate to severe chronic graft-vs-host disease [GVHD]. We all agree that that’s where systemic immune suppression is generally required. There’s clearly a role for topical immunosuppression for individuals with mild disease, treating the eye, mouth, and local areas of skin with both topical immunosuppression [and] topical supportive care. Hydration, keeping the skin and eyes moist, and other issues like that. Let’s talk mainly about the treatment of moderate to severe chronic graft-vs-host disease. The state of affairs…is once again the use of corticosteroids. We can’t seem to get away from this compound that we love and hate. The dosing of steroids here is a little bit different than in the acute GVHD setting. We typically do not use higher doses of steroids, limiting ourselves to either 1/2 to 1 mg/kilo per day, or even every other day, as the initial therapy. We’ve tried to improve upon that as initial therapy. Doris, do you want to tell us about some of the initial therapy trials in chronic GVHD that unfortunately have not been terribly successful?

Doris M. Ponce, MD: In the chronic graft-vs-host disease arena, we’ve been trying to incorporate different agents to treat chronic graft-vs-host disease. At least that I remember, mycophenolate was one of them [used to try] to help improvement of chronic graft-vs-host disease. Higher-dose corticosteroid has been explored as well where the end point and the NRM [nonrelapse mortality] was actually not successful. The patient had a higher risk of infection and inferior NRM.

Corey Cutler, MD, MPH, FRCPC: The most important recent clinical trial in the initial therapy of chronic GVHD is the trial that added ibrutinib to steroids, which was a randomized trial that compared ibrutinib plus corticosteroids to steroids alone.

Doris M. Ponce, MD: We have new armamentaria that we are excited about because we didn’t have anything before. We have ibrutinib, which was approved after a phase 2 clinical trial where a patient with chronic graft-vs-host disease was treated after failure to corticosteroids. This clinical trial shows a promising response, and they achieved their primary end point, and based on that, the drug was approved. We also have [ruxolitinib], as you know. This is the REACH3 trial [NCT03112603], where ruxolitinib was used in the setting of a steroid-refractory chronic graft-vs-host disease. For this trial, the dose of ruxolitinib was a bit higher. They started with 10 mg twice a day as their standard. This was compared with best available therapy. It was a phase 3 randomized trial, and the ruxolitinib arm was successful. Their treatment response was about 50%. Correct me if I’m wrong, but it’s still successful as best available therapy. The last one to mention is belumosudil. That was used, but [the trial was for] more advanced chronic graft-vs-host disease patients who had failed multiple lines of therapy, more than 2. The cutoff was up to 5. In that clinical trial, they show superior oral response in the belumosudil arm. What’s interesting is that they look into a subset study, and even [in] a patient who had multiple lines of therapy and by organ assessment, it was promising in the subset analysis.

Corey Cutler, MD, MPH, FRCPC: That’s a very good overview of the currently approved FDA agents. To take a step back, in the upfront setting, it’s still steroids alone. The trial I was going to speak about was steroids plus ibrutinib vs steroids alone in the upfront, which did not improve the response rate, although there were some signals that perhaps there was an enhanced ability to taper corticosteroids a little bit earlier and perhaps a prolongation in the failure-free survival. The other trial that’s probably worth mentioning is the [BMT] CTN-0801 study [NCT01106833] that looked early on at the addition of extracorporeal phototherapy. That arm was dropped, but the other alternative strategy in that trial was the discontinuation of the calcineurin inhibitor and the addition of sirolimus. There was a hint in this randomized phase 2 setting that perhaps the addition of sirolimus or an mTOR inhibitor upfront might improve response rates. Actually, that’s something that I do in my clinical practice. Historically, many of us used to give steroids plus calcineurin inhibitors when we started steroids for chronic GVHD. I’ve actually switched to give sirolimus in patients who had previously received it and who tolerated it. In particular, in those patients who recently were tapered off of it as their primary immunosuppressive. Yi-Bin, do you give anything with steroids upfront? Do you give a calcineurin [inhibitor], or give sirolimus?

Yi-Bin Chen, MD: I don’t. I personally don’t feel that the calcineurin inhibitors have much of a role in treating chronic graft-vs-host disease, so even if I don’t add it back, I don’t increase it back to therapeutic target, or anything like that. I might not stop it, but I don’t use it as a primary form of treatment for new chronic GVHD. Another trial we should mention that was presented at ASH [American Society of Hematology annual meeting] this year for upfront chronic [GVHD] where we tried to improve upon it, but we did not, was GRAVITAS-309 [NCT03584516]. This was a large phase 3 effort that was planned to test the combination of steroids plus the JAK1 inhibitor itacitinib as the initial therapy of chronic GVHD. There was sort of a complicated design of different arms to find the right dose and so forth, but the bottom line was that the trial was closed prematurely while there was some signal of increased overall responses in those patients. There’s definitely more unacceptable toxicity in the patients who received itacitinib. It illustrates a couple of things. One is that these chronic graft-vs-host disease patients are often fragile from the journey that they’ve been through. Many of them have had prior acute GVHD and previous long courses of steroids. The second thing is that unlike what we talked about in acute GVHD, and this may be something to expand on, is that we don’t have a way to risk-stratify chronic graft-vs-host disease patients. So, it’s oftentimes difficult to think [about] as you’re enrolling all of these patients, and they’re so heterogeneous with different organ manifestations and different stages of disease. When they present and when we’re diagnosing it, how are we going to make progress and show improvement?

Corey Cutler, MD, MPH, FRCPC: There is a risk-scoring system for chronic graft-vs-host disease that the CIBMTR [Center for International Blood and Marrow Transplant Research ]came up with a number of years ago, first published in Blood by Mukta Arora [MD]. I actually use the risk-scoring system when I diagnose my patients with chronic GVHD. It divides patients into about 6 categories based on risk, and it can be prognostic. That risk stratification scheme is now perhaps a little old. It was done largely in the pre- [and] post-transplant…setting, and so its utility moving forward may be limited. But up until now, I’ve been at least using that to give my patients a sense of how their chronic GVHD was going to go.

Transcript edited for clarity.

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