Transplant-Associated GvHD - Episode 3
Understanding the importance of having a multidisciplinary team in the treatment of acute GVHD, panelists discuss the NCCN Guidelines and REACH2 trial.
Yi-Bin Chen, MD: Dr Munshi, you had mentioned that when patients are first admitted to the hospital, you engage other services to help patients with acute GVHD [graft vs host disease]. Can you describe when a patient is in the hospital with GI [gastrointestinal] GVHD? Dr Chao had mentioned the long road to recovery. We’re familiar that this patient has weeks ahead in the hospital to slowly recover. What other supportive care is engaged for this patient to recover?
Pashna N. Munshi, MD: These patients don’t feel the brunt of the steroids and the first week that they get such high doses, but it’s very quick. It all catches up: They get myopathy, and they get very weak and debilitated. I’m quick to engage physical therapy and occupational therapy up front for these patients to prevent disability and long-term disability. Somebody who’s having this degree of the area is depleted of protein and calories; they get malnourished quickly. As much as we want to maintain enteral feeding, in an acute setting gut rest is warranted to prevent the extra absorption and output. I put them on clear liquids and start them on TPN [total parenteral nutrition] for a short time to give them a little break.
Yi-Bin Chen, MD: A team approach is needed to help the patient recover from this type of complication. There is literature on this, as we treat patients who had an initial endoscopy to get a biopsy. Dr Chao, does your center do serial endoscopy in these patients to help assess the response or figure out what’s going on?
Nelson Chao, MD: We will do a second biopsy sometimes when patients are not getting better, just to be sure we’re not missing something like CMV [cytomegalovirus]. It’s not to see if they start GVH but to be sure there aren’t other reasons for their diarrhea.
Yi-Bin Chen, MD: There’s some literature, mostly pediatric, that when you look at these biopsies in patients who have steroid-refractory acute graft vs host disease being tested, oftentimes when you focus on mucositis, you may see that a good amount of these patients have thrombotic microangiopathy localized in the GI tract. There’s some literature that the endothelium itself is a target organ of acute graft vs host disease. Do you look for that in your patients, Dr Chao? How does that play into what options you can select from management?
Nelson Chao, MD: We’ve been slow to come around to realizing the endothelium as a target for a lot of what we do in terms of damage. Encephalitis has been mostly understood in the COVID-19 era, but we do the same thing with the PrEP [pre-exposure prophylaxis] regimens that we use with the TBI [total body radiation]. That synthesizes a lot of the toxicity between GVHD, VOD [veno-occlusive disease], SOS [sinusoidal obstruction syndrome], and TMA [thrombotic microangiopathy]. For microangiopathy, in many ways it could be a spectrum of endothelial injury and attempts to recover. We do look at TMA for adults; we’re way behind the pediatricians. They’re more attuned to it, and we don’t pay as much attention as we should.
Yi-Bin Chen, MD: I agree. It’s good to see some research starting in this area. The next few years will shed more light on this to help us understand. We should mention that for this indication of steroid-refractory acute graft vs host disease, the FDA in May 2019 approved the agent ruxolitinib for adult patients who started with refractory acute graft vs host disease. This becomes 1 additional option. As far as the case goes, the patient herself was then started on ruxolitinib at 5 mg twice a day and subsequently increased the dose to 10 mg twice a day when it was apparent she was tolerating the drug quite well. The NCCN [National Comprehensive Cancer Network] has had recently formed a panel for transplant and transplant complications. The consensus panel thought it was reasonable to treat steroid-refractory acute graft vs host disease. Dr Munshi, does this list look comprehensive to you as agents that you or your group think about when contemplating treatment for such patients?
Pashna N. Munshi, MD: This is quite a large list but not something unknown to us all. At any given time we’ve tried several of these agents, not quite in this order, but whatever anyone’s comfortable using in this room. Everyone has their preferences. ECP [external counterpulsation] is commonly used depending on if it’s available at peoples’ centers and infliximab if it’s lower GI GVHD. Some of my colleagues use ruxolitinib quite frequently as well as ATG [anti-thymocyte globulin]. There’s a whole variety of choices, but the response rates are similar. I’m not enthusiastic about 1 vs another. We’ll look at the data to come for ruxolitinib. Maybe that might be game changing.
Yi-Bin Chen, MD: Do you mind going through the data for the REACH2 trial that validated ruxolitinib as a standard of care in this setting?
Pashna N. Munshi, MD: This was a phase 3 study done outside the US. It was in patients with steroid-refractory acute GVHD who were randomized 1:1 to receive ruxolitinib 10 mg twice a day with steroids, with or without a calcineurin inhibitor, vs best-supportive therapy with steroids with or without calcineurin inhibitor. The best-supportive therapy was chosen based on these 9 agents that are commonly used in Europe based on their guidelines and all of which we have used as well in the United States. These patients were allowed an optional crossover, and the primary end point was the overall response rate at day 28. The secondary end points were to look at the durability of responses on day 56. Other key secondary end points were also failure-free survival, event-free survival, and nonrelapse mortality. The population did include pediatric patients as well. The age limit started with 12 years and above, including the adult population, and patients had to have myeloablative and naturally were excluded if they had an active infection or severe organ failure.
Looking at the primary end point of overall responses at day 28, ruxolitinib had an overall response rate of 62% with 34% complete responses, compared with the control arm, which had an overall response rate of 29% and about 19% complete responses. This seems to be a big difference when you look at quick responses to something that’s refractory to steroids. In the secondary end point, looking at the durability of these overall responses at day 56, you can see that ruxolitinib had a 40% durable overall response at day 56 with about 27% of these patients having incomplete responses and about 22% overall having durable responses in the control group. Those patients who were in CR [complete remission] seemed to have maintained these responses even at day 56. What is nice about these data is that several patients were able to come off their steroids by day 56, achieving these responses. At least about 21% of these patients were able to discontinue their steroids by day 56 in the ruxolitinib arm.
If you look at the response duration, it looks at the loss of responses at 6 months as part of the secondary end point. It was about 10% in the ruxolitinib arm compared with 39% in the control arm. These data weren’t statistically significant, but when you look at the survival curves, they do separate. In terms of failure-free survival, which was another secondary end point for this trial, designed to compare survival outcomes. The data weren’t statistically significant, but if you look at that the curves do separate on the median failure-free survival 5 months in the ruxolitinib arm compared with 1 month in the control-arm. The failure-free survival means that these were patients, who from randomization to the first relapse, at the time of needing more therapy in addition to steroids, or death due to nonrelapse or nondisease causes constituted failure-free survival. When looking at the adverse events—none of which is unknown to us—we’re familiar with all of them. Most patients on ruxolitinib really had thrombocytopenia, anemia, and CMV infections, more in the ruxolitinib arm compared with the control group. All these seem to be managed well, and there were some stopping rules. If patients couldn’t be supported with low platelet counts, then they could come off the ruxolitinib or both could receive platelet transfusions.
Yi-Bin Chen, MD: Thank you very much, Dr Munshi.
This transcript has been edited for quality.