Transplant-Associated GvHD - Episode 2

Case 1: Treatment for Steroid-Refractory Acute GVHD

Experts discuss the treatment considerations for acute GVHD, the role of molecular testing, and considerations for steroid-refractory acute GVHD.

Yi-Bin Chen, MD: In the last few years, from a lot of work from MAGIC [Mount Sinai Acute GVHD International Consortium], there have been a couple of blood-based biomarkers that have been defined in certain contexts for acute graft vs host disease [GVHD]. They revolve around mucosal damage and include the proteins ST2 and REG3α. That’s a commercially available test. Dr Chao, do you think there’s validity to send these biomarkers? Do they help you in any way?

Nelson Chao, MD: There’s validity to these markers. Through the MAGIC consortium, they’ve done a good job identifying and validating them. We have not used this routinely, although we have used it at times when we were not sure what’s going on with the patient. I want to remind everybody that these symptoms of a rash and a biopsy showing some changes can happen with a lot of different things. There are times when it’s not so clear whether the patient has GVHD. In those cases, we added these tests to get a sense of whether that helps you. It’s still a clinical diagnosis.

Yi-Bin Chen, MD: Dr Munshi, would you agree?

Pashna N. Munshi, MD: I agree. This is a hot topic of discussion among us. How we use this in our practice is variable across different centers. With MAGIC lookup being based on the algorithm, you can potentially predict who’s going to have severe GVHD. But how we use those numbers, especially in response to treatment, is still a little unclear to me. I still rely on the clinical aspect of treatment for these patients and use the clinical scoring as an indicator for treatment and response.

Yi-Bin Chen, MD: These biomarkers, as both of you have mentioned, have been validated in certain contexts and certainly can stratify groups, but no prospective trial has shown that we should treat those patients differently or that treating them differently results in us being able to influence the outcomes. Trials done this way, involving the biomarkers, will help elucidate this in the future. It’s an exciting area moving forward. Let’s move on to more of the case.

Pashna N. Munshi, MD: She was initiated with IV methylprednisolone, 1 mg/kg per day, which is standard systemic steroid therapy. On day 3 of the steroid therapy, her diarrhea increased to 1500 cc per day, and she developed abdominal pain, though the skin rash began to fade. The bilirubin remained at 2.5 mg/dL. The dose of methylprednisolone was subsequently increased to 2 mg/kg per day; it was doubled. After 4 days at this high dose, there was minimal improvement of diarrhea and abdominal pain. The rash was fading, but the bilirubin was increased to 3 mg/dL.

Yi-Bin Chen, MD: At this point, Dr Munshi, would you consider this patient to be steroid-refractory?

Pashna N. Munshi, MD: I would. Based on the criteria and definitions used in clinical trials, patients who seem to have worsening disease at the third day or greater than three days after initiation of steroids, those who need a dose escalation in the steroids, or who haven’t responded by day seven, meet the definition of steroid-refractory acute GVHD. In her case, she meets all those criteria.

Yi-Bin Chen, MD: Dr Chao, based on your experience, this is a patient who’s a month out from transplant with steroid-refractory acute graft vs host disease that now involves the lower GI [gastrointestinal] tract, meeting a certain severity with over 1500 cc a day of diarrhea. What’s been the experience with these patients in terms of prognosis?

Nelson Chao, MD: The worst patients are those who have refractory liver, but right after that are those who have lower GI involvement. They have a long road ahead if they’re going to get better, and frequently they don’t. It becomes quite problematic.

Yi-Bin Chen, MD: What do you think looking forward for this patient? Could you give an estimate on what you think their 1-year survival is at this point?

Nelson Chao, MD: It’s hard to tell because they failed steroids alone. With second-line therapies, there’s still a chance that they may respond. It’s hard to tell. Had she responded already, she would have been much better. She still has a high risk of continuing to progress or just not get better completely.

Yi-Bin Chen, MD: Dr Munshi, because this patient meets the criteria for being considered steroid-refractory, what would be your next step in managing this patient? There are a couple of options. Would you keep the steroids on for longer and see if there’s a response? Would you add another agent? Do you do anything else for this patient at the moment?

Pashna N. Munshi, MD: Meeting the criteria for steroid-refractory GVHD, she needs something in addition to steroids. Stopping the steroids at this time is not a great option because the flare could worsen. People still need steroids, but they need another mechanism of action, getting in there and breaking down the GVHD cycle.

Yi-Bin Chen, MD: In retrospect, one could have asked, “Should this patient have started 2 mg/kg at the beginning?” That’s asked only in retrospect. We all acknowledge that steroids somewhere between 1 and 2 mg/kg per day is standard. Most of us try to spare steroids when we can. But at this point, another agent is warranted. Dr Chao, do you agree?

Nelson Chao, MD: I do. There was a study that Paul Martin had in Seattle showing that 2 mg didn’t add much more than the 1 mg/kg. We all do it. I would do the same thing. I don’t know that I would have served it to the patient, but the patient should get something else. It brings up an interesting question, which is that we do this routinely. We add things to steroids, and I’m not sure that makes biological sense and steroids aren’t working. We don’t add a second or third antibiotic of the same class because the first 1 didn’t work. I’ve often wondered whether we do more harm by not trying to get patients off steroids. We just keep adding stuff.

Yi-Bin Chen, MD: When we add a second agent, we try to lower the steroids, acknowledging that because steroids aren’t working, why would we keep them at the same dose anyway? There is toxicity that we are all aware of with steroids. One of my pet peeves is, while I agree with everyone, we would add another agent at this point to not only improve the clinical response but also spare the exposure to steroids. We’re not great at judging the response of GI GVHD, because we’re measuring the volume of diarrhea each day, which seems primitive in terms of trying to understand what’s biologically occurring. In the future, whether it’s biomarkers or something else, we need a more accurate way to understand what’s happening because the GI tract takes time to re-epithelialize to see a response.

This transcript has been edited for clarity.