The Expanding Field of GVHD - Episode 6
Comprehensive discussion on the treatment options available for patients diagnosed with steroid-refractory acute GVHD.
Corey Cutler, MD, MPH, FRCPC: Given a patient with acute graft-vs-host disease in front of us, we do have to treat these patients. GVHD [graft-vs-host disease] if left untreated, progresses and ultimately is fatal in the absence of a therapeutic intervention. Unfortunately, in 2022, our mainstay for a therapeutic intervention remains corticosteroids, with 1 small exception. Steroids are both our friend and our enemy in this setting. We tend to administer steroids at doses between 1 and 2 mg/kg per day, depending on the degree of organ involvement. Steroids are toxic; they have a number of adverse effects, [including] glucose control impairment, increasing risks of infection, myopathy, weakness, psychological effects, etc. We’ve long been looking for alternatives or different ways to treat our patients, but thus far, nothing has been proven to be superior to steroids in the upfront setting for the management of acute graft-vs-host disease.
The 1 exception to this is a study that was performed by the BMT CTN [Blood and Marrow Transplant Clinical Trials Network] and led by Joseph Pidala [MD, PhD,] that used biomarkers, as Yi-Bin just mentioned, and included only patients who had lower risk biomarker scores at the time of their enrollment. It randomized patients to receive either standard steroids or sirolimus, which is an mTOR inhibitor and a profound immunosuppressant. It turned out that patients who were risk-stratified to not have the highest rates of bad acute graft-vs-host disease, so the Ann Arbor [staging] groups 1 and 2, those subjects who were randomized to receive sirolimus rather than prednisone, had outcomes that were essentially the same as those who received prednisone.
The study was small and couldn’t measure quality-of-life effects, but it stands to reason that patients who do not receive steroids for management of their limited stage GVHD fared better from a quality-of-life point of view. At our center, we’ve adopted this strategy, a number of us have, even in the absence of the use of a biomarker. [For] patients with very limited skin stage-only acute graft-vs-host diseasewho I think need systemic rather than topical immune suppression, I will try them on sirolimus first. That is a little different than the outline of the clinical trial.
Now, steroids are good. They will result in remission in about 70% to 75% of our patients, of whom at least a third will have recurrent acute GVHD symptoms as we try to taper their steroids. Perhaps 50% of our patients with acute GVHD go on to require a second-line agent or an agent for steroid-refractory acute GVHD. Yi-Bin, would you briefly tell us what the definitions of steroid-refractory acute GVHD are, and what’s your approach to the treatment of these patients?
Yi-Bin Chen, MD: Sure. You’ve hinted at a couple of the different definitions. There have been 3 major definitions of steroid-refractory graft-vs-host disease in the acute setting that have often been studied together in clinical trials. The first are patients who clearly progress after at least 3 days on high-dose systemic corticosteroids. You can tell who these patients are because [after] 3 days on high-dose steroids, if they look worse, you know they’re not going to get better. The second population is those you’ve treated with high-dose steroids for at least 1 week, and it’s not that they’re getting worse, but they’re not getting better. These patients have fit the bill for steroid-refractory as well. Then the third population is the population you referred to, patients who have [an] initial response to steroids, usually a partial response. Then as you start to taper steroids in hopes of avoiding the morbidity associated with prolonged corticosteroid use, they have a flare of their acute graft-vs-host disease symptoms again and require re-escalation of steroids. Those are the 3 populations. They’ve unfortunately been lumped together in clinical trials to study steroid-refractory acute graft-vs-host disease, purely from a practical number standpoint, but they’re different populations. They likely have different biologies, especially the patient who never responds and gets worse after 3 days vs the one who responds first and flares. Those are biologically different populations.
These days we’re not shy about adding a second agent. If a patient meets any of those definitions, we’re usually very quick to add a second agent to help. That’s partly because we are somewhat cautious and wary about the toxicities of long-term steroids. It’s partly because we now have a standard of care for steroid-refractory acute graft-vs-host disease. That is ruxolitinib, which is the first approved agent for steroid-refractory acute graft-vs-host disease based on the REACH1 and REACH2 clinical trials. Here at Massachusetts General Hospital, if someone has cutaneous-only disease, and they’re started on high-dose steroids and they have steroid-refractory disease that’s restricted to the skin, we’re very quick to add ruxolitinib. Then we try to taper those steroids because they’re steroid refractory. If patients have lower GI [gastrointestinal] disease, which the steroid-refractory population is enriched for lower GI disease, our standard, which is probably different from others, our standard off clinical trials is the combination of ruxolitinib plus vedolizumab, the monoclonal antibody that targets the alpha 4, beta 7 integrin that is approved for inflammatory bowel disease. That’s admittedly probably not the standard at other institutions. It’s our own interest and experience with vedolizumab, but that’s our standard of care.
I should mention we obviously try to have clinical trial options open for all of these patients with steroid-refractory disease because even with the approval of ruxolitinib, we still believe there’s a lot more room for improvement. The options of the past that we used prior to ruxolitinib, the majority were globally immunosuppressive. They were rooted in this belief that acute graft-vs-host disease is a T-cell response, and we should target the T cells themselves, such as with ATG [antithymocyte globulin] or alemtuzumab. Or we should target the inflammatory pathways that might contribute to the persistence of inflammation driven by these T cells, such as targeting IL-2 [interleukin-2] or the TNF [tumor necrosis factor] alpha cascade, and so forth. We rarely use these agents anymore.
Usually, after ruxolitinib and vedolizumab, if another agent is needed, we’re looking at things like ECP [extracorporeal photopheresis] or photopheresis, given the less globally immunosuppressive effects, as well as thinking about things like fecal microbiota transplantation, which is another area we’ll touch on. I think in general, the field itself is moving away from global immunosuppression because it didn’t help patients and contributed to their demise from opportunistic infection, and focusing more on things like organ resilience to promote healing and allow patients to hopefully survive through what’s generally a very difficult time.
Transcript edited for clarity.