Unmet Needs in GVHD

Video

Challenges and unmet needs in steroid-refractory GVHD and advice to community oncologists for the optimal management of disease.

Yi-Bin Chen, MD: There’s still a lot of room for improvement in research in acute graft-vs-host disease [GVHD], specifically for steroid-refractory acute graft-vs-host disease. While ruxolitinib was approved in 2019 and does help a subset of patients, it is not a home run. There are many patients who either don’t respond at first or don’t have a durable remission after an initial response. Ruxolitinib is definitely progress, but we need more research into steroid-refractory acute graft-vs-host disease. You can come at it from several perspectives. We can develop better drugs or better agents to treat steroid-refractory acute GVHD, or we can say that we should do a better job preventing patients from even getting there. That means better initial therapy or better prevention.

There is a lot of work and investigation in novel agents. We’re moving in the right direction by getting away from cumulative immunosuppression from additional agents and focusing more on targeting specific inflammatory pathways or even organ resilience and trying to preserve the intestinal stem cells, especially for patients with acute lower GI [gastrointestinal] GVHD.

All the work that’s being done in biomarkers will hopefully help us better risk-stratify patients to do trials with a patient population that’s more homogeneous. These biomarkers can hopefully also help us complement our clinical judgment to understand how patients are really doing and better judge response. Maybe they could ultimately even serve as end points in clinical trials moving forward.

Corey S. Cutler, MD, MPH, FRCPC: For steroid-refractory chronic GVHD, the greatest challenge right now is understanding which drug will work in a given patient. The drugs that are approved or we are anticipating approval on work by very different mechanisms, and we have not yet determined which agent is the right one for each individual patient. We also have no great way of identifying patients who appear to have JAK-STAT–dependent GVHD or ROCK2-dependent GVHD. It is quite possible that we will not be able to determine which drug will work for which patient. We are going to need to learn how to sequence these drugs properly, as we have several drugs approved with overlapping approval and indications. We’re going to have to learn how to use these drugs rationally in combinatorial therapy and to determine whether combinatorial therapy is in fact better than single-drug therapy for chronic GVHD.

GVHD remains in the realm of the transplant center, and I would encourage community physicians to be in touch with the transplant center where the patient was initially treated. They can often provide some good advice through either telemedicine or telehealth and would like to partner in treating these patients to achieve the optimal outcome. Screening for chronic GVHD is important in the community. Finding the earliest signs of ocular, oral, and cutaneous disease is critical so that we don’t end up with long-term sequelae of chronic GVHD that might have been prevented by earlier recognition and treatment of chronic graft-vs-host disease.

Haris Ali, MD: For any patient with acute GVHD, because it can be rapidly progressive, we would strongly encourage this patient to be referred back to their treating transplant physician so they can get effective treatment. It can become steroid-refractory and then they may require many specialized treatments, including clinical trials. Time can be lost if they don’t get to the clinical trials or more intensive treatment for acute GVHD.

For chronic GVHD, you can start a patient on steroids. I would definitely consider referring this patient to a transplant center because of the availability of clinical trials and multidisciplinary care. These patients are also at risk for many other problems, including steroid-induced adverse effects, opportunistic infection, and severe muscle weakness. Those can be appropriately addressed at a transplant center by a multidisciplinary team.

Yi-Bin Chen, MD: The main priority for us as a community moving forward should be to continue to do well-thought out, collaborative clinical trials to make improvement. For acute graft-vs-host disease, there are ongoing efforts in prevention. Hopefully we’ll see the results of those large trials soon to understand if they will change the standard of care. For the initial treatment of acute graft-vs-host disease, the future is to better be able to risk-stratify our patients, to take the high-risk patients and treat them in clinical trials that add drugs to steroids to increase the chance of a meaningful clinical response. For the lower-risk patients, it’s actually to decrease therapy. It may be to not use steroids and use a different drug. If we do use steroids, once you achieve a response, we want to prescribe a rapid tapered steroid to spare the patient the exposure to steroids. That’s the way moving forward for acute GVHD that we’re going to make some more progress.

For chronic graft-vs-host disease, a good amount of research is ongoing. We expect approval of a couple of agents in this coming year. That’s very exciting for the field and for our patients. Akin to acute GVHD, it would be better to risk-stratify chronic graft-vs-host disease through a biomarker signal and be able to develop different treatments for biologically different patients.

For providers who are treating patients with chronic graft-vs-host disease, a lot of it is about reframing expectations. Once you develop chronic graft-vs-host disease, the statistics would say that there’s a good chance you’ll be on lifelong medication for it and will be managing it basically forever. It’s about helping patients understand that. It’s not about expecting that we should get back to normal at that point, but that we need to stop progression of the disease and then slowly make it better, while understanding that the statistics would suggest you’re going to be on chronic therapy for a long time. Once we understand and accept that, we’ll be able to better understand how to improve the lives for our patients going forward.

Transcript Edited for Clarity

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