Transplant-Associated GvHD - Episode 6

Case 2: REACH3 Trial

The experts discuss the REACH3 trial in steroid-refractory chronic GVHD and what they hope to see in the future of treating chronic GVHD.

Yi-Bin Chen, MD: There are recent interesting results presented at both the American Society of Hematology and the ASCCT [American Society for Cellular and Computational Toxicology] meetings on the results of phase 3 REACH3 clinical trial. Dr Chao, do you mind taking us through that?

Nelson Chao, MD: This was presented in these past 2 meetings as a prospective randomized trial looking at ruxolitinib versus the best alternative therapy. The primary end point was overall response rate, which was 50% for [ruxolitinib] compared to 26% for the best alternative therapy. The CR [complete response] rate was 34% versus 19%. P value was .001. The secondary end point was the modified Lee Symptom Scale improvement, and that was significantly better for those patients with [ruxolitinib] compared to the best alternative therapy. Failure-free survival was not reached with the [ruxolitinib] group compared to the best alternative therapy, both statistically significant. Overall response, CR was reached in 11 patients versus 5. PR [partial response] was 71 versus 37, with an overall response rate of 50% for the [ruxolitinib] compared to 26% for the best alternative therapy, statistically significant. Adverse events were not terrible with [ruxolitinib]; as you would expect, there was more anemia because of the impact on hematopoiesis, but overall it was quite well tolerated. The overall anemia, hypertension, pyrexia, and elevation in ALT [alanine transaminase] was not prohibitive. Infections were higher in terms of fungal and viral, but not very different from the best alternative therapy.

Yi-Bin Chen, MD: We all expect based on these pivotal results that ruxolitinib, which is already approved for steroid-refractory acute graft-versus-host disease, may gain approval for steroid-refractory chronic graft-versus-host disease, as those were the patients in the REACH3 trial. Does this trial or the upcoming approval change your standard of care for steroid-refractory chronic graft-versus-host disease?

Pashna N. Munshi, MD: We still would like to see the data mature, but in my practice, this is an off-label use. I still use it in my patients, ones who might be eligible or might benefit. When we see data that are convincing, those of us who haven’t been using it a lot might want to use it more, and those who have been using it might feel more justified in using this treatment. I don’t know if it’s entirely practice-changing in that sense. Chronic GVHD is dynamic, and it requires various aspects of care, not just 1 drug or 1 type of therapy. There are different mechanisms all over the place going on that need to be targeted.

Yi-Bin Chen, MD: Dr Chao, where does ruxolitinib stand in your list of options for steroid-refractory chronic graft-versus-host disease? Are there any other factors, clinical or otherwise, that you use to choose a therapy for a specific patient?

Nelson Chao, MD: I wish we would understand better the factors that could make a difference and choose differently for different patients. Right now, our go-to is either [ruxolitinib] or ECP [extracorporeal photopheresis]. If a patient is relatively close, we tend to use ECP because, not that it’s easy to use, but it doesn’t cause as much of the systemic immunosuppression that other agents have. If they’re not close we do use [ruxolitinib]. As you saw from the data, there is plenty of room for improvement, and [ruxolitinib] is good. It did have statistical differences to the best alternative therapy, but there is plenty of room for improvement.

Yi-Bin Chen, MD: I would agree with that. But also it may be that we have to change our expectations in the sense that every agent we’ve tested, we have this metric for complete remission or CR. I am not sure how realistic that is for someone with established chronic graft-versus-host disease. Maybe we need better drugs, and if a drug comes along that yields a significant CR rate, I’ll be the first to be corrected and use it. The overall response rate, while better than the control, has room for improvement, but the CR rate does as well. We measure response by NIH [National Institutes of Health] criteria, and sometimes the partial response is meaningful, and other times it is not life-changing or meaningful at all. There is validation in the incorporation of the patient-reported outcomes as they did, and that was reassuring. We use ruxolitinib, here in Boston, for steroid-refractory chronic graft-versus-host disease. But I agree with you, we do use ECP as well, and oftentimes the choice is based on the logistics for the patient, what they are able to do, and how far away they live.

Nelson Chao, MD: We need for chronic disease studies to show VGPR [very good partial response] because we have patients who you can’t call CR because if their skin is tagged down and fibrotic, that’s never going to get better, but the patient’s performance status is 100%. At that point, if they are on 7.5 mg of prednisone for the past 6 months and they are doing great, you can’t call that patient a CR, but for practical purposes, the patient is doing very well.

Yi-Bin Chen, MD: I agree, and for patients with severe ocular disease, who now have specialized lenses, we can never expect their eyes to get better, but we can treat them for other manifestations that make this huge difference. There are a couple of other agents that had interesting results presented at these last couple of meetings. There is a company called Kadmon [Holdings, Inc], and their agent KD025 or belumosudil, is a ROCK2 inhibitor targeting fibrosis with interesting results. Do you have any thoughts on the data that were presented for KD025?

Pashna N. Munshi, MD: It’s exciting to see anything that has great responses. Everything is relative, but this was a phase 2 trial. It was a smaller study, and they were comparing a 200-mg daily dose with a twice-a-day dose, and it has a different mechanism of action from JAK1 inhibition. The overall response rate was 73% for the daily dosing and a similar response rate for the BID [twice-a-day] dosing. At this point, the data continue to mature, but it looks like there were almost 50% of responders who could maintain these responses at 20 weeks. That is exciting to have in the chronic GVHD realm.

Yi-Bin Chen, MD: I would agree. Dr Chao, any thoughts in the sense that this appears to be where we are moving in terms of testing agents that are no longer globally immunosuppressive, but target more specific inflammatory pathways? Do you think that’s the right way we should be going for this disease?

Nelson Chao, MD: It think it is. What was remarkable about belumosudil was that it was remarkably well tolerated. The AEs [adverse effects] were pretty mild, so that’s encouraging. Targeting the fibrotic pathways is what will make a difference, not just broadly inflammation, but fibrosis is one of the major problems we have run into with this disease.

Yi-Bin Chen, MD: That’s the histological hallmark when we biopsy tissue, and many have questioned, by the time you’re treating the patient with established disease, is it no longer a classical immunological disease in terms of allogenic or autoimmunity, but rather more of a fibrotic disease? The other agent that some of us have been involved with, in terms of participating trials, is an agent made by the company Syndax [Pharmaceuticals, Inc] called SNDX-6352. It’s a monoclonal antibody that’s targeted against activated macrophages. Any thoughts on that Dr Chao, experience, or hopes for that agent?

Nelson Chao, MD: That’s a good segue to your earlier comment about trying to target these fibrotic pathways. CSF1R, which is what this is targeting, is an important survival and growth factor for these macrophages. We know that, not so much in graft-versus-host disease, but in other fibrotic pathways that macrophages are very important. We do know, they are old data now, that once you have the activated T cells that cause GVHD, those can get removed, and GVHD continues based on these other myeloid cells that cause the downstream effects. It makes sense to try to target these pathways.

Yi-Bin Chen, MD: Dr Munshi, looking forward, is there anything that you think that the field needs to focus on in chronic graft-versus-host disease research, and in the next few years what are you looking forward to?

Pashna N. Munshi, MD: I would like to see what we can do with some of these combination therapies that are steroid-sparing, and see if we can move them into the frontline setting and target specific changes and organs effectively mechanistically together, rather than using steroids as a one-stop shop for all organs. Every organ behaves differently in a chronic GVHD setting, there might be a fibrotic mechanism, but the eyes behave differently, and then maybe the gut behaves differently. We need to think about the individual person rather than treating all patients with chronic GVHD similarly as one.

Yi-Bin Chen, MD: Dr Chao?

Nelson Chao, MD: I agree, I couldn’t have it said any better.

Yi-Bin Chen, MD: There are recent studies presented that have started to quantify the burden or toxicity of steroid use in our patients and these patients going forward. That’s one avenue forward because that can serve as an end point if we start to quantify what the toxicity and burden is, and we conduct trials in terms of being able to not only spare steroids but maybe even replace steroids for a specific subset of patients. Are we able to develop some system, be it clinical or biological, in terms of biomarkers to be able to risk-stratify our patients to conduct trials? As you are saying, Dr Munshi, not treating everyone the same, and being able to offer low-risk patients steroid-free regimens, and be able to better categorize these patients to ultimately improve their outcomes.

I want to thank our panel for the thoughtful case presentations and the informative discussion. Thank you for joining us for this Targeted Oncology™ Virtual Tumor Board® presentation. We hope today’s discussion was a valuable use of your time and that you acquire practical knowledge that can ultimately help you in your clinical practice. Thank you very much.

This transcript has been edited for clarity.