Dr. Yi-Bin Chen:
Welcome to The ASCO Post Roundtable Series on Chronic Graft-vs-Host Disease. My name is Dr. Yi-Bin Chen. I'm Director of the Transplant Program at Massachusetts General Hospital and faculty at Harvard Medical School. Joining me today is one of my colleagues, Dr. Mitch Horwitz.
Dr. Mitch Horwitz:
Hello, my name is Mitch Horwitz. I'm the Director of Adult Blood and Marrow Transplantation at Duke University Medical Center in Durham, North Carolina.
Dr. Chen:
In this installment, we'll be discussing chronic graft-vs-host disease and the importance of early intervention for patients who do not have a complete response to first-line treatment with corticosteroids. Let's get to the case. So this case is a 65-year-old female with inversion 16 acute myeloid leukemia, who's in second complete remission. She had not underwent transplant initially, because of her favorable karyotype. But unfortunately, relapsed, and now, has achieved second complete remission. Standard of care now would be to pursue an allogeneic hematopoietic cell transplant for curative potential. Because of her age, she underwent reduced intensity conditioning with fludarabine and busulfan, and she received a matched unrelated donor peripheral blood stem cell graft with tacrolimus and methotrexate graft-vs-host disease prophylaxis. During her transplant course, she experienced some mild mucositis, but ultimately, recovered uneventfully with full donor engraftment.
In the first 3 months afterwards, she was followed, as one would expect, and did not have any issues with acute graft-vs-host disease or other significant complications. Around day 100, the tacrolimus taper was started. Right around day 150, so about 5 months after her transplant, in follow up, she presented with eyes that were quite dry, requiring the use of artificial tears more than 10 times a day for symptomatic improvement. Her mouth was a bit dry having to, she described as having to drink more water during meals to be able to swallow her food. Upon physical exam, she had an erythematous maculopapular rash on the trunk of her skin, and on laboratory investigation, she had elevated transaminases, about three to four times the upper limit of normal. So at that point in time, giving the multiorgan involvement of what appeared to be chronic graft-vs-host disease, she was started on systemic prednisone at a dose of 0.5 mg/kg/d. I'm just going to stop right there and ask Dr. Horwitz. Mitch, would this be standard first-line treatment for chronic graft-vs-host disease?
Dr. Horwitz:
Yes, as much as I would like to have other options for patients, particularly patients in the 60 to 70 year age group, corticosteroids are the first-line therapy for patients who develop chronic graft-vs-host disease, often very effective. In fact, it continues to be the most effective modality we have for chronic graft-vs-host disease, but there are certainly significant downsides that most practitioners realize. And these get more significant the longer and the higher the dose is. There's always a question as to what dose to start with, but I think this was an appropriate dose, given the patient's age and the severity of the chronic GVHD manifestations.
Dr. Chen:
Yeah. My next question was going to be, are you happy with the first-line treatment? But I think we can sense that you're not happy adding prednisone, and I'm not either. And I think that both of us and others in the field hope that, one day, we've advanced to where we're giving steroid-free treatment for first-line therapy or much lower dose steroids, but we have to do those trials to figure it out. I agree with you. It doesn't make me happy when I have to start steroids, even at this dose, for an older patient, at this point in time after transplant. I think, while they do respond, we pay for it later in terms of chronic morbidity, and we probably don't taper it fast enough either. But this patient, as you indicated, one would expect to have a reasonable response to steroids.
She was able to achieve a partial remission in all organs and did feel better in the early course while on steroids. And so, usually after a few weeks of that steroid dose and all organs responding, we try to taper the steroids, as happened here. So her provider did taper the steroids, but what was observed, from about the 6-month to the almost about the 1-year mark, was that, every time the steroids were tapered below about 0.25 mg/kg/d, her skin rash flared. And that's a flare. And this case really gets at steroid dependent chronic graft-vs-host disease then, and each time, her steroids were then raised back up to 0.5 mg/kg or a dose that brought the skin rash under control. Finally, around the 1-year mark, ruxolitinib was added at 10 mg orally twice a day for second-line treatment. So what do you think about that? The conventional teaching had been, if disease flared while tapering steroids, to increase the steroids to recapture a response. And this was done several times here, and ultimately, ruxolitinib was added.
Dr. Horwitz:
I think this is a situation, where, if you're a community oncologist listening, this is where there needs to be a continuity and consultation with the transplant physician. There's an inclination to continue to raise the steroid dose, because it does work. Even for patients demonstrating steroid dependence, raising the dose often will resolve the rash. Patients will often be miserable with pruritus, and in the short term, it seems to help. But what this case demonstrates, and we can talk about, if you'd like, even the timing of the availability of second-line agents that have come online, that have really changed our ability to manage patients like this safely and minimize their exposure to corticosteroids.
Dr. Chen:
Yeah, let's touch on that. So Mitch, you're getting at recent approvals in chronic graft-vs-host disease, and I'll just mention them. We have ruxolitinib, which is the JAK1, JAK2 inhibitor. We have ibrutinib, which is the oral BTK inhibitor, which are both approved for second-line therapy. And then, we have belumosudil, which is a ROCK2 inhibitor, which is approved for third-line therapy for chronic graft-vs-host disease. I think it's great that we have access to these agents and options for our patients. Has sort of access and approval of these agents, has that changed your threshold to move past steroids in these patients?
Dr. Horwitz:
Absolutely. And even as a transplant physician, who's had the benefit of being specialized in my field, the rapidity of new options, relatively speaking, is unprecedented in our field, that typically moves much slower. So as you point out, there are two agents now, that could be used in the second line. And for those of us who, and all of us really, it's not just me, who abhor using corticosteroids at moderate doses for any length of period of time, I'm definitely using and declaring steroid dependence or steroid refractory. So it should be pointed out that it doesn't necessarily mean to use the second-line agent doesn't require steroid refractoriness.
Most of our patients will respond to some degree, but you see often, more times than not, see what you're seeing in this patient, which is that, as soon as you get down below a certain threshold, there's a recurrence of the symptoms, whether it be the skin or the mouth irritation. Some of the other findings that we're seeing in this patient, such as the dry mouth and the dry eyes, can't necessarily be used as a marker for disease activity. Those are problems that may persist for many months, even years, and don't represent active disease. But the liver function test abnormalities, the maculopapular rash, the injected sclera, those are signals of persistent disease and would, in my mind, trigger the use of a second-line agent.
Dr. Chen:
Yeah, I couldn't agree more. It really gets at thinking about what's our indication now to move to second-line therapy. If you just pull up titles or abstracts of the trials that were responsible for approvals of the agents that we just mentioned, one might read that they were approved for steroid-refractory disease or failure of one agent. You really have to think about what failure means, as that is our current standard of care to move on. And then, I would summarize it this way, there are patients that just get worse, despite starting steroids, and that's easy. That's clearly refractory. There are those that don't get better. So after a few weeks of steroids, if the disease is stable, while that is a goal of therapy that we give to halt progression, we shouldn't be happy with that.
Dr. Horwitz:
That's not satisfactory.
Dr. Chen:
And that's another indication to start. I think the two other indications, some of which are illustrated here, are you can get a partial response with steroids. But you could just not be happy with it. You and the patient have to talk about if that's a satisfactory response from a quality of life perspective. You can get what's defined as a NIH partial response, but that, in no way, can be satisfactory to you or the patient. And so, to make the partial response better is another indication why we might move on to second-line therapy. And then, the fourth indication would be, you responded, but you know you can't get the steroids off. So to spare your patient the long-term morbidity of the steroids, adding a second-line agent, as is illustrated here, if they keep flaring, would be the fourth reason to do so.
I just think those are important reasons to lay out for people treating patients with chronic graft-vs-host disease. And I couldn't agree with you more that keeping up communication with the transplant center, if you're out in the community, is essential to being able to figure out how to use these new medicines. For this patient, after adding ruxolitinib, the rash did respond. Per the transplant provider, it looked like the chronic graft-vs-host disease was in a good place, and the steroids were actually able to be tapered off. Now, the patient did not have a CR or a complete remission of chronic graft-vs-host disease, which, in all honesty, is rare, but maintained a partial remission, but importantly, was able to taper off steroids by 18 months. I think we wonder if we had added the ruxolitinib earlier in the course, rather than go through cycles of steroids, if we could have gotten off steroids a lot sooner.
And that is one goal for us going forward here. I think that illustrates why I think you've heard Mitch and I both feel that early intervention for steroid refractory disease is where we're all going. This patient had around 2 years, presented with fever, shortness of breath, classic URI symptoms that we see here in New England winters and was diagnosed with a RSV infection, which she recovered from. But three weeks later, she presented with worsened shortness of breath and hypoxia. And imaging with a chest CT showed diffuse ground glass opacities and thickened small airways.
The patient, at that point, was diagnosed with sort of a postviral COP or cryptogenic organizing pneumonia and started on steroids. Now, she proceeded on steroids. Again, not happy we had to add steroids, but we did for standard of care for this sort of entity. And over a few months, the patient was tapered off these steroids out. Ultimately, we, at 2.5 years, we repeated her imaging and her pulmonary function test, and clearly, she had now developed obstructive disease consistent with bronchiolitis obliterans syndrome. Mitch, so I just want your opinion here, in terms of, do you see this where we have chronic graft-vs-host disease, we treat patients, we think they're in a much better place, and they develop some infection and that sort of triggers everything all over again?
Dr. Horwitz:
Absolutely. I think this can happen at any time during the course. We know, even early on, patients who develop transient bacteremias in their first month or two after transplant are at higher risk for acute graft-vs-host disease. So it makes sense if you think about a patient who's trying to reconstitute immunity and then is challenged with viruses or bacteremias or whatever triggering inflammation. And that could then lead to this alloreactive pathology or we call graft-vs-host disease. And this case demonstrates one of the most insidious and vexing problems that we need to deal with in such patients that that is chronic graft-vs-host disease of a lung.
So we never know when it transitions from an infection, such as what was clearly a viral infection here, to chronic graft-vs-host disease or persistent viral infections. I've had patients with rhinovirus for months, shedding rhinovirus, and sometimes, it finally goes away. And other times, it just transitions into graft-vs-host disease of the lung. And I wish we could have a good ending to this story, but this patient is already on a second-line agent. Perhaps, one could try a third-line agent. There are other agents to try, but in fact, we need to get better at managing these kinds of problems. And I think it serves to let the managing physician know that, when you have an infection, a pestering infection, after an allogeneic transplant, that these types of problems need to be brought to the attention of the managing transplanter.
Dr. Chen:
I think that the key clinical takeaways from this case would be that initial therapy of chronic graft-vs-host disease with corticosteroids leads to suboptimal outcomes in the majority of patients. Ensuring patients having follow up at appropriate intervals to evaluate response and to initiate second-line therapy if needed, is essential to optimize outcomes in chronic graft-vs-host disease. As we mentioned, ruxolitinib and ibrutinib are both now FDA approved for second-line therapy of chronic graft-vs-host disease, with ruxolitinib included as the only NCCN category 1 recommendations, supported by a phase III randomized controlled trial. In addition, belumosudil is approved for third-line therapy of chronic graft-vs-host disease, as well. The access and the approval of these agents has truly transformed the way we take care of these patients.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in chronic GVHD or visit ascopost.com.
