Insights From: Yi-Bin A. Chen, MD, Massachusetts General Hospital; Zachariah M. DeFilipp, MD, Massachusetts General Hospital; Colleen M. Danielson, NP, Massachusetts General Hospital
Yi-Bin A. Chen, MD: With that initial therapeutic approach, [the results of] large studies have shown that even with some success, still greater than 50% of patients will require a second agent and thus meet the definition for steroid-refractory acute graft-versus-host disease. And it goes without saying that most of the complications experienced by patients with acute graft-versus-host disease are in this group—what we call the steroid-refractory group. Historically, clinical trials have been very difficult to conduct in this group, partly because of the relatively small number of patients at each center and the heterogeneous definition of steroid refractory as well as the heterogeneity of the patients.
And probably most importantly, clinical trials have been difficult to conduct because of competing risks in this population. They’re so sick, as you’ve heard from both Coleen and Zack. And so, even if you give an effective agent, sometimes your patient dies from complications before you can understand whether that agent is going to work or not. So it’s a very, very difficult population to study as well as to improve.
The definitions of steroid refractory have been different. I think the most obvious one is patients who start on what Zack has described as the initial therapy and get worse. So you have a patient who comes in with a liter of diarrhea. You start 2 mg/kg per day of steroids, and by day 4 they’re at 5 liters of diarrhea. It’s easy to see that those steroids are not working. The second group of patients are patients who just don’t get better. So patients who come in with 2 liters of diarrhea and after 14 days of the same steroid dose are still at 2 liters of diarrhea are clearly not improving. So they haven’t gotten worse but they’re just not getting better. The third group of patients whose graft-versus-host disease is categorized as steroid-refractory are patients who actually have an initial response, but then, as you start to lower the steroids in that first month to try and avoid those adverse effects, as Zack was discussing, the patients experience a flare and get worse again. So those 3 situations are what trigger us to add second-line therapy. We are still, as Coleen is pointing out, measuring the volume of diarrhea each day, looking at the rash, and looking at the bilirubin. These, admittedly, are fairly primitive markers, but they are the best we have.
Zack hinted at research looking at novel biomarkers of graft-versus-host disease to help risk-stratify patients. These same biomarkers—Reg3α and ST2—are being studied to hopefully help us understand how patients are doing as we treat them. So we’re engaged with this MAGIC [Mount Sinai Acute GVHD International Consortium] and other studies to try and figure out if there are biomarkers or blood tests that can help us understand how patients are going to do, not just look at how much diarrhea they’re having or what their skin rash is. Hopefully, we’re able to define these biomarkers, which can truly help us improve care.
Until recently, there were no FDA-approved treatments for acute graft-versus-host disease. Even what we have used for the last decades, steroids, were not technically FDA approved. But recently, we’ve had our first agent, which is very exciting, become FDA approved for graft-versus-host disease—ruxolitinib. But the agents in the past that we’ve used include many options. They have historically been studied in other diseases and then were repurposed for graft-versus-host disease. Historically, they’ve targeted the immune system because, intuitively, graft-versus-host disease is an immune response, so trying to treat it 1 way would be to suppress the immune system.
So our historical treatments that we’ve used for steroid-refractory acute graft-versus-host disease have been agents such as anti-thymocyte globulin; other immunosuppressants, such as sirolimus and mycophenolate mofetil; and pathway inhibitors such as etanercept or denileukin diftitox. Newer agents that we’re looking at do not suppress the immune system globally but instead target specific pathways to hopefully specifically shut down graft-versus-host disease while sparing the immune system and not accruing as many adverse effects.