Video
Treatment Armamentarium for Steroid-Refractory Chronic GVHD
Comprehensive discussion on each of the 3 standard-of-care treatment options for patients with steroid refractory chronic GVHD.
Transcript:
Corey Cutler, MD, MPH, FRCPC: Let’s go through those 3 FDA-approved agents. We’ll start with ibrutinib, which was the first agent approved in this setting. Much of the background for this comes from work at Dana-Farber Cancer Institute that suggested that B cells are quite important in the etiology of chronic graft-vs-host disease [GVHD]. Among others, we did studies demonstrating that B-cell–directed therapy can treat established chronic GVHD. Ibrutinib is a Bruton tyrosine kinase inhibitor, which we all use in diseases like CLL [chronic lymphocytic leukemia] and mantle cell lymphoma because of its effects on the B cell. A single-arm open-labeled study in 42 subjects was able to demonstrate that two-thirds of subjects who were enrolled had meaningful responses to ibrutinib in the second line.
There were a couple of caveats to that trial. The patients were a highly select group of subjects. They had to have early and inflammatory manifestations of their chronic GVHD to be enrolled. Many of them were not steroid refractory but were steroid dependent. The trial was well designed with the FDA in mind. Based on the results of that trial, the drug was approved. Many of us have started to use ibrutinib a little less in the real-world setting because of its effectiveness in later-stage scleroderma or fibrotic stage chronic GVHD and because of the appearance of other agents on the market. Ibrutinib is generally well tolerated. It does have gastrointestinal adverse effects. It can impair platelets to some degree. There’s some fatigue and muscle cramps associated with it. But in general, it’s a drug that’s tolerated reasonably well.
The third drug, which I’m going to tap Yi-Bin to speak about, is ruxolitinib. This was while the first drug approved for acute GVHD. In fact, it was the third drug approved in chronic GVHD. I’m going to ask Yi-Bin to review some of the data that led to its approval and how he sees its role in chronic GVHD.
Yi-Bin Chen, MD: As we mentioned, ruxolitinib was first approved for the treatment of steroid-refractory acute graft-vs-host disease. Because of its approval for the treatment of myeloproliferative diseases, many of us in the field were quite comfortable with it. There’s a lot of enthusiasm for using ruxolitinib because it’s oral and well tolerated. But we don’t know exactly how it works. There’s a lot of signaling through the JAK1 and JAK2, where a lot of inflammatory signals go. Inhibiting the signaling through those nodes appears to have some effect. There’s some effect on T-cell migration, regulatory T-cells, macrophages, and NK [natural killer] cells. It seems to have broad effects, but clinically there have been beneficial outcomes for certain patients with graft-vs-host disease.
It was approved in September 2021 for the treatment of steroid-refractory chronic graft-vs-host disease. This was on the heels of the REACH3 clinical trial. This was a trial conducted here in the United States as well as internationally. It was a phase 3 trial that randomized patients with steroid-refractory chronic graft-vs-host disease to ruxolitinib vs a control called best-available therapy. Since there’s no standard that’s recognized that the control arm had to be a menu of options that investigators could choose. This trial randomized 329 patients to either ruxolitinib or best-available therapy. The primary end point was the overall response rate at 24 weeks—round 6 months—which is appropriate for a disease such as chronic graft-vs-host disease. The results of the study showed that in patients who received ruxolitinib, about 50% achieved an overall response, whereas only 25% of patients who received the other treatments had an overall response. That led to its approval.
There were clear advantages for ruxolitinib with the end point of failure-free survival, and quality of life, as measured by our instruments and use. With that approval, at the majority of centers I collaborate with, ruxolitinib has become the standard of care for second-line systemic therapy for chronic graft-vs-host disease. It’s fairly easy to use as an oral agent twice a day. The main adverse events are what people are already familiar with from having used [ruxolitinib] in other settings, which can cause anemia and thrombocytopenia due to its effect on EPO [erythropoietin] and TPO [thrombopoietin] signaling. That’s a real effect, and a certain subset of patients cannot tolerate ruxolitinib, though many can be managed with dose reductions as well as knowledge of drug-drug interactions.
We use a good deal of ruxolitinib. We reach for it for steroid nonresponsive chronic GVHD, but also if you get a partial response that’s not good enough for the patient or yourself. We add on ruxolitinib not only to improve that response but also to spare patients’ steroids. That’s been a big advance in our field: the use of ruxolitinib in this disease.
Corey Cutler, MD, MPH, FRCPC: I agree. The important thing to come out from REACH3 is that even though the best-available therapy arm was a collection of agents that many of us don’t consider active at all, the overall response rate in the best-available arm was 50%—not measured at week 24, but overall—and the overall response of ruxolitinib was higher at 75%, which affirms its activity. Linda, what’s your experience with ibrutinib and ruxolitinib. How do you choose between these 2 agents before we get into the third-line drug?
Linda Perry, PA-C: By far, we’re definitely more of a ruxolitinib-oriented center. There are definitely a handful of patients for whom we’ll use ibrutinib. But to be honest, even before ruxolitinib was approved, we had shied away from ibrutinib and toward ruxolitinib. Our experience was with a very select group of populations with oral involvement, the erythematous skin rash, so many of our patients don’t necessarily fill the bill.
We definitely favor ruxolitinib. To echo everything you’ve said, early initiation is key. We’re not waiting for these patients to have that complete response on steroids. It’s probably not going to happen. The minute we need to start somebody on systemic therapy or steroids, we’re putting through that prescription with the intent that we will start it right away. Even though the indication is for steroid-refractory, we’re starting it almost simultaneously with the steroids to get a jump-start.
Corey Cutler, MD, MPH, FRCPC: That’s interesting that you can get approval in that setting. It’s important that we talk about the second drug that was approved for chronic graft-vs-host disease. This is the first drug designed for the chronic GVHD space. This is belumosudil, which was the second drug approved in summer 2021 for the management of steroid-refractory chronic graft-vs-host disease. It was approved on the basis of a randomized phase 2 trial. This is a study where we randomly assigned 62 subjects to 1 of 2 doses each of belumosudil, either once-a-day or twice-daily dosing. We were able to demonstrate that about 75% had meaningful responses to belumosudil therapy. The responses were durable. The time on the drug approached a year when we put out our first reports. We’ve got follow-up reports now. There are clear advantages in terms of patient-reported outcomes using the Lee Symptom Scale.
Belumosudil is an interesting compound because we think it affects chronic graft-vs-host disease in 2 ways. The first is at the level of the germinal center, where we think GVHD immune responses occur, and it can rebalance immunity there by shifting a pro-inflammatory Th17 [T-helper 17 cell] response to a somewhat more anti-inflammatory T-helper cell response by changing STAT3 and STAT5 signaling. That’s the classic way of thinking about it as an effective agent in chronic GVHD. The novel way that belumosudil might be helpful is the way it can prevent or even reverse scarring. Belumosudil is an inhibitor of the ROCK2 enzyme. ROCK2 is important for the final stages of scarring and fibrosis. It impacts myofibroblast migration and the way it lays down collagen. This drug can prevent or reverse some of the scarring associated with chronic GVHD.
Interestingly, in a forthcoming paper, we were able to demonstrate that this drug can reverse some of the lung changes or bronchiolitis obliterans changes that are seen in some patients. This is the first time an immunosuppressive drug for chronic GVHD has been able to reverse changes. There are several examples of other immunosuppressants, including ruxolitinib, steroids, and ECP [extracorporeal photopheresis], that can halt the progression of BOS [bronchiolitis obliterans syndrome]. But this is the first time we’re demonstrating improvements in lung function. It’s an exciting compound, and we’re going to see this drug tested in a number of other clinical scenarios.
Transcript edited for clarity.
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