Defining steroid-refractory acute GVHD, treatment options for patients who don’t respond to steroid therapy, and a review of the REACH2 trial.
Yi-Bin Chen, MD: Steroid-refractory acute graft-vs-host disease [GVHD] has generally included 3 different patient groups. After we start initial therapy with high-dose systemic steroids, if patients are clearly getting worse after 3 days, which generally means another organ is involved or the initial organ is definitively getting worse, that is steroid-refractory. If patients receive initial steroids and haven’t gotten better after a week of that dose, that also meets the definition of steroid-refractory. The third definition is probably a more favorable group of patients. This involves patients who initially responded to steroids, either achieving a partial response or a complete response for acute graft-vs-host disease, and then upon attempts to taper steroids, their symptoms of graft-vs-host disease flared. This last group is probably more favorable. They’ve often been included in clinical trials for steroid-refractory graft-vs-host disease. Perhaps they’re more accurately referred to as steroid-dependent.
In our practice, we are fairly quick to add a second-line therapy. Your motivations to add another therapy for the treatment of acute graft-vs-host disease are 2-fold. You want to improve the response and treat the graft-vs-host disease more. You also want to spare the patient a significant exposure to high-dose steroids, because while steroids can be very helpful for certain conditions, such as graft-vs-host disease, we can all accept that long-term steroids have a bunch of toxicities, including immunosuppression, high blood pressure, osteoporosis, mood effects, and many others.
Our triggers generally follow the definition of steroid-refractory. If patients are getting worse after 3 days or not getting better after 7, we add a second agent. Also if patients experience a flare of symptoms upon tapering of steroids, somewhat dependent upon dose, we will add a second agent. There are patients who we know won’t do well with steroids. These include patients who are brittle diabetics, have horrible osteoporosis, or are already quite deconditioned and weak from other complications. In those situations, our triggers to add a second agent may be lower to spare the patient exposure to steroids.
Haris Ali, MD: Patients who have failed steroids for treatment of acute GVHD, their outcome is quite poor, so they need effective treatment. Currently, the only approved treatment for these patients is ruxolitinib, which is FDA-approved for treatment of steroid-refractory acute GVHD. Some of the other options besides ruxolitinib, which I use as off-label, are various immunosuppressants, including basiliximab, infliximab, photopheresis, ATG [antithymocyte globulin], and rituximab.
Corey S. Cutler, MD, MPH, FRCPC: The only agent that’s approved for steroid-refractory acute GVHD is ruxolitinib. It was approved on the basis of the REACH1 and REACH2 studies. REACH2 was a randomized trial in which slightly over 300 subjects were randomized to receive either ruxolitinib or best-available care according to investigator choice. Very importantly, at day 28, the response rate in the ruxolitinib group was a little over 60%, whereas in the control arm it was just under 40%. That’s about a 50% improvement at day 28 response rates. By day 56, there was unfortunately a diminution in the response rate in both the ruxolitinib and the control arm. The ruxolitinib response rate fell from about 62% to just under 40%, so almost a third of the subjects lost their response, whereas in the control arm, about 50% of subjects lost their response, from almost 40% to just over 20%. This solidifies the role of ruxolitinib in the therapy of steroid-refractory acute GVHD. However, it does tell us that there is still room for improvement in this space. We’re actively testing other agents to see if we can find something that will be complementary to ruxolitinib or potentially even better.
Haris Ali, MD: The FDA approved ruxolitinib for the treatment of acute GVHD based on the REACH1 trial, which was an open-label, single-arm trial that showed response rates up to 55% to 60% in these patients. REACH2 was another very important trial that compared a larger portion of patients to best available therapy. It gave more definitive data, and you’re comparing it with the other standard therapy, which showed that ruxolitinib was very effective in controlling steroid-refractory acute GVHD. That confirmed the findings and improved clinicians’ confidence that this is effective for treatment of acute GVHD.
Ruxolitinib was used by many clinicians even prior to the FDA approval because of the data presented by the German group that showed the response rates were close to 70% to 80%. At that time, it already had quite a buzz. People were using it because it was available and in the market. These data just increased the use of it because some of the other clinicians did not see it as approved and insurance would not approve it. With it now approved, more patients are able to get the medication.
Yi-Bin Chen, MD: We have had a rather favorable experience using ruxolitinib for steroid-refractory acute graft-vs-host disease. It’s a drug that we’ve been familiar with for years because it’s been approved for other diagnoses, and it definitely has an effect and brings about a response in a certain portion of patients. It’s not a home run, meaning it certainly doesn’t work for 100% of patients. And as you’d expect, the patients who are the highest risk and most predicted to respond least well to any therapy are the same with ruxolitinib. These are people with severe lower GI [gastrointestinal] disease. In our experience, patients with skin-only disease respond extraordinarily well to ruxolitinib, while those with liver and GI disease respond a bit less well. That’s anecdotal. It’s not published, but that’s been our experience. However, we still have no hesitation using ruxolitinib for any organ involvement for steroid-refractory acute graft-vs-host disease.
From a toxicity perspective, it has been very well tolerated. The main issues are what has been described. There is a certain subset of patients who will develop cytopenias, mainly thrombocytopenia and anemia, with the use of ruxolitinib. We have found that these can usually be accommodated with dose adjustments. Rarely have we had to stop the agent itself.
Corey S. Cutler, MD, MPH, FRCPC: When choosing an agent for steroid-refractory, both acute and chronic GVHD, one has to look at what type of adverse effects the patient already has and what you believe the patient can tolerate based on the drug you’re going to choose. We know that agents such as ruxolitinib and the other JAK inhibitors cause some modest cytopenias, and therefore, one has to be careful when starting this agent in patients who have platelet counts below 30,000 to 50,000 per mm3. If monitored very closely, you can often overcome the shortcomings, but you do have to pay close attention, particularly to thrombocytopenia and the risk of bleeding if patients fall below 10,000 per mm3. One has to be very careful globally in both acute and chronic GVHD to prevent infection by piling on immune suppression to patients who are already suppressed with corticosteroids. It does leave patients open to further risk of infection. Therefore, prophylactic antibiotics, prophylactic antifungals, and potentially antivirals, particularly against CMV [cytomegalovirus], are very important supportive care measures to improve outcomes in acute and chronic GVHD.
Transcript Edited for Clarity