Steroid Refractory Acute GvHD and REACH Trials

Video

An overview of steroid refractory acute GvHD and a review of the REACH trials that assessed the used of ruxolitinib in patients with GvHD.

Transcript:

Corey Cutler, MD, MPH, FRCPC: Standard or even higher-risk disease remains a bigger problem. We’ve been trying to find better therapeutics than steroid monotherapy. Unfortunately, a very large, randomized trial that included itacitinib as up-front therapy for acute GVHD [graft-vs-host disease] was not a positive study not that long ago. At ASH [American Society of Hematology Annual Meeting], we saw a randomized trial that looked at ruxolitinib in combination with corticosteroids for the up-front therapy of acute GVHD. Tell us your initial impressions on that.

Yi-Bin Chen, MD: This a study that many of us have been asking for based on the success of ruxolitinib specifically but for JAK inhibitors in general. In the treatment of graft-vs-host disease, many patients have wanted to see the use of JAK inhibitors in earlier lines, either in the initial treatment or even in prevention. The abstract that you’re referencing is a phase 3 trial out of China that randomized patients with newly diagnosed grades 2 through 4 acute GVHD to either of the standard steroids alone. There wasn’t a placebo, and the experimental arm was steroids plus ruxolitinib. Their results showed a much higher overall response rate and better outcomes in patients who received steroids plus ruxolitinib and the ability to taper steroids faster. Although their long-term outcomes probably required some more longer follow-ups, they were comparable for the patients partly because patients who failed steroids alone were allowed to cross over. That always muddies your long-term survival outcomes.

The trial is super interesting. They risk stratified patients by biomarkers and we’d love to see the biomarker distribution in the details. Only about 30% of patients had lower–GI [gastrointestinal] disease on that trial. We like to see more details of the patients themselves. Also, the transplant setting in China is a bit different from what it is [in the United States] and other parts of the world. Their most common donor source is haploidentical transplants, and it’s not based on a post-transplant cyclophosphamide platform. You wonder about GVHD and how generalizable is it. Nevertheless, it’s a super-interesting study, and we’d like to apply it to other settings or see more details.

Hannah K. Choe, MD: Correct me if I’m wrong, but did they also lower the dose of the steroids with the ruxolitinib arm too? It’s actually 2 mg vs 1 mg plus ruxolitinib.

Corey Cutler, MD, MPH, FRCPC: Would it be safe to say that it’s exciting and provocative data, but perhaps not enough to change the standard of care in North America right now?

Yi-Bin Chen, MD: I think so. We need to see full details. It would be great to see full details in the manuscript.

Doris M. Ponce, MD: It’s important to highlight something that caught my eye, which was a very high CR [complete response] rate in the patient. When we assess treatment response, partial response is considered successful, but it’s even more successful if you achieve CR. In that study, they had a high rate of CR. It’s like raising the bar of how we want to achieve that initial response, and studying this platform in the future with our patient population may be more representative of what we do. It could be a practice change.

Hannah K. Choe, MD: As you pointed out, if it wasn’t as much lower-GI involvement than that, CR rate is naturally going to be higher too. We see that in our patients.

Corey Cutler, MD, MPH, FRCPC: We’re trying to improve up-front steroid therapy and up-front therapy in general for acute GVHD. Despite high rates of CR in the ruxolitinib trial, we know that that’s not what we see in clinical practice. Tell us, Hannah, what does steroid-refractory acute GVHD entail?

Hannah K. Choe, MD: Steroid-refractory acute GVHD assumes that you’re on usually 2 mg/kg of steroids and that after 3 to 5 days either progressing, or after 7 days of not responding. It becomes a little difficult because there are so many fluctuations in the small amounts of diarrhea that can change. When patients are that sick, there are a lot of other things happening at the same time. Generally, it depends on the time, duration, and dose of the steroids.

Corey Cutler, MD, MPH, FRCPC: In the steroid-refractory setting, what do you even do with the actual doses of steroids? If your patient isn’t getting the response they need, you’re going to reach for another agent. Do you keep the steroids going at that dose? Do you taper? What’s your approach?

Yi-Bin Chen, MD: In the true steroid-refractory patients, using the definitions Hannah laid out, steroids aren’t working and trials done a long time ago with even higher-dose steroids suggested that that was harmful. In a setting of true steroid-refractory disease, based on progression after 3 days or not getting better after 7, we reach very quickly for a second-line agent. In general, that’s ruxolitinib. At Mass General [Massachusetts General Hospital], if it’s lower-GI disease, we add vedolizumab with ruxolitinib; that’s our institutional practice.

Then we immediately start to taper steroids because the rationale is that they’re not working, so they can only be harming at that point. We don’t stop them; we just tapered them. As the patient gets better, we hopefully taper more. In the trials over the last couple of decades, there’s another definition of steroid refractory: patients who have responded and then, as you taper the steroids, flare. That’s better to call steroid dependent, but they’ve been lumped into steroid refractory, often muddying the interpretation of trials. In that setting, if you call that patient steroid refractory, you might increase the steroids back to a certain level, depending on where you are, to recapture response while adding a second agent. It depends on the situation.

Corey Cutler, MD, MPH, FRCPC: When we talk about ruxolitinib as the preferred second agent, that’s on the basis of 1 important trial. Walk us through the REACH studies and how we got to ruxolitinib as an approved agent in steroid-refractory acute GVHD.

Doris M. Ponce, MD: REACH2 was a novel clinical trial design in which patients with steroid-refractory acute graft-vs-host disease were randomized between ruxolitinib or the best-available therapy. They were called a control in the clinical data. Their primary end point was day 28 treatment response. They also assess other end points such as day 56 treatment durational response. In general, the study drug was well tolerated. There were similar adverse events between the 2, except for thrombocytopenia and CMV [cytomegalovirus] viremia incidence was higher in the ruxolitinib arm. Now, day 28 treatment response was a success. Patients had a high treatment response of about 63%, which was superior to control arm. They also had a superior day 56 treatment response. Treatment failure was lower in patients on ruxolitinib. Based on that, the FDA approved the study drug, ruxolitinib.

Corey Cutler, MD, MPH, FRCPC: We have roughly a 60% response rate for steroid-refractory disease. But as you mentioned, at day 56, there was a loss of response, so we’re clearly not done in terms of therapeutics in steroid-refractory or steroid-dependent acute graft-vs-host disease.

Transcript edited for clarity.

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