Case 2: Treating Steroid-Refractory Acute Graft-Versus-Host Disease

Bart L. Scott, MD: How quickly do I determine whether a patient is steroid-refractory or steroid-dependent? I generally wait 3 to 5 days. If patients have persistent symptoms after 3 to 5 days of therapy with high-dose steroids, then I would classify them as being steroid-refractory.

How often in my experience is acute GvHD [graft-versus-host disease] refractory to corticosteroids? I would say about one-third of the time, so approximately 30% of patients develop steroid-refractory GvHD. This is based on data from a randomized trial comparing 2 mg/kg with 5 mg/kg of steroid therapy, as initial treatments for acute graft-versus-host-disease.

That trial showed no benefit with giving the 5 mg/kg dose, and that’s why the 2 mg/kg dose is what we consider to be more of a standard upfront steroid dose. But in that trial, the arms show about a 30% refractory rate to steroids for the treatment of acute GvHD.

What is the trigger to start second-line therapy? It is primarily persistent symptoms. That can be very difficult, honestly, and that gets into the art of medicine. The rash may not be completely resolved, but it should, in my opinion, be changing colors. It shifts from being more of a bright red intense color to more of a port wine color that’s more deep purple. The itching also rapidly improves if a patient is responding.

In regard to the GI [gastrointestinal] tract, the diarrhea should definitely be improving. The increased stool frequency may not be completely gone, but the consistency of the stools should be shifting from liquid to more of a solid base, so more of a mushy base. Certainly there should not be any more GI tract bleeding, and there should not be any more completely undigested food. The abdominal cramping, abdominal pain should be improved and resolved. But admittedly, these are somewhat subjective, and it does get into the art of medicine. It is 1 of the more difficult things that I have to do when following a patient.

Is it better to react sooner than wait? In my opinion, yes. If patients have untreated acute GvHD, that is very bad. This is particularly if patients have persistent symptoms after steroid therapy. What happens with GvHD is that you get cellular mediated damage of the GI tract, the skin, and the liver. That releases antigens into the circulatory system, which then upregulate continued cytotoxic T-cell response. In essence there’s an auto amplification loop that’s built into graft-versus-host disease.

You need to get on top of that inflammatory cascade as soon as possible. If you don’t stop the ongoing T-cell mediated damage, then patients, of course, can die from graft-versus-host disease. We see this most clearly when patients have GI tract symptoms. So if there’s any question whether the patient is having continued symptoms, it’s better to err on overtreating than undertreating.

Our nurses are on the front line, and they generally get the first telephone calls when a patient develops acute GvHD. All patients who undergo transplant at our center are told multiple times what the symptoms of acute GvHD are—skin rash, nausea, vomiting, diarrhea, abdominal pain, liver function abnormalities. We monitor patients very closely for any of these symptoms. We’re open 24 hours a day every day. If patients develop symptoms over the weekend, there’s always a triage system that’s built in. No patients who develop GvHD symptoms should wait, even if it’s in the middle of the night. So that’s an important message to send to the patient.

In regard to the pharmacists, they play an important role because we all work together to make sure the patients have therapeutic drug levels. Many of the medications that we give for treating GvHD, such as tacrolimus and sirolimus—we have targeted drug levels—so we work with the pharmacist to make sure that the patient is taking the correct dose, whether they’re receiving that for prevention or for treatment of acute GvHD.

As I mentioned, the nurses are really on the front line. In the hospital setting they round with us every day with the patients. They’re the ones who actually are tracking the stool output, so they have the best input into how much stool a patient is actually having, what the consistency of the stools are for instance if there’s undigested food, and those types of things. In each patient’s room, we have a big meeting with the nursing staff, with the pharmacists, the residents, and the attending physician, all giving their input at the same time. So it is really a team approach to ensure that the patients have the best outcome.

It’s important to get the help of the patient because if they don’t tell us about their symptoms, or they let their symptoms go, then of course we don’t start treatment on time and patients can have a negative outcome.

What is the incidence of acute GvHD after transplant in the patient population at our center? That is variable, depending on donor status and depending on GvHD prophylaxis. But just taking the most common approaches, we generally give methotrexate GvHD prophylaxis for patients who have matched sibling donors and matched unrelated donors. For the matched sibling donors, our incidence of developing grade 2 to 4 GvHD is approximately 40%. For matched unrelated donors, our incidence developing grade 2 to 4 GvHD is approximately 60%.

What are the expectations surrounding treatment and supportive care? Our expectation is to involve the patient so that they let us know as soon as any symptoms may develop. We do have clinical trials that are in place for patients who develop acute GvHD. If they do develop it, our primary goal is to try to enroll them into 1 of these clinical trials with the effort to improve overall outcomes. If they’re not eligible for a clinical trial, then our initial treatment for acute GvHD would typically be sirolimus or steroid therapy.

The REACH2 trial was a pivotal phase 3 trial that compared ruxolitinib, given at 10 mg twice daily, to investigator choice for patients who developed steroid-refractory acute graft-versus-host disease.

It was a very important study because it’s 1 of the few studies that we have that actually shows a benefit for treating steroid-refractory acute GvHD. The patients were randomized to either receive ruxolitinib or investigator choice. For investigator choice, there were several different options. One option was extracorporeal photopheresis. But regardless of whatever the physician chose, ruxolitinib essentially won out and had better overall response rates.

For patients who develop steroid-refractory acute GvHD, based on the REACH2 trial, I think ruxolitinib should be considered the standard approach. Of course, the option of enrolling patients into a clinical trial is still there, but that would be the big change. We would generally start patients on ruxolitinib or enroll them into a clinical trial if they are eligible.

Transcript edited for clarity.