Treating Chronic GVHD After Allogeneic Transplant for IDH2-Mutated AML
In this video, Yi-Bin Chen, MD, Massachusetts General Hospital, Boston, discusses the treatment course for a patient with chronic GVHD after receipt of an allogeneic stem cell transplant for IDH2-Mutated AML, spanning multiple lines of therapy.
Transcript:
Hi, my name is Yi-Bin Chen. I'm the director of the Hematopoietic Cell Transplant and Cell Therapy Program here at Massachusetts General Hospital in Boston. It's my pleasure to be here today to talk about this case, which is based on a true story from one of my patients. She had acute myeloid leukemia. With an older patient in her 60s, we felt, as did her local physician, that hematopoietic cell transplant in remission would be her best chance at a durable remission and potential cure, if we dare to say that.
What's interesting about her was that she is active and healthy. When they did her workup, at first, an echocardiogram showed that she had asymptomatic, moderate aortic stenosis. She never knew that, never had any symptoms from it, and she actually tolerated conventional induction therapy with an anthracycline and cytarabine fine, as well as a second induction course, because she had residual disease and one cycle of cytarabine-based consolidation. So really had a stress test already for her heart. But we were aware of her valve going into this.
She's in her 60s, and so we offered her reduced intensity conditioning with fludarabine melphalan. We did identify a fully matched unrelated donor. And one of the biggest improvements in transplant over the last 10 years would be improvements in the prevention of both acute and chronic graft-versus-host disease (GVHD). Probably the biggest advance would be, as most know, the emergence of post-transplant, high-dose cyclophosphamide, that platform, which is proven to be safe, certainly in the older population as well.
These days, we tend to give less cyclophosphamide than what is published. At MGH we do 40 milligrams per kilogram per day on days 3 and 4 instead of the published 50. We find that to be better tolerated and certainly for someone who's elderly with cardiac concerns, that's what we would do, pairing that with tacrolimus and mycophenolate.
She went through her transplant course rather well. Engrafted, got out of the hospital, and then we had her go back to Maine. We did see her weekly for follow-up for the first couple of months, and then she was able to transition back to her local doctor. And then we had a shared care model where she would come see us every month and we'd communicate very closely with her local physician while we were tapering her immunosuppression.
But at 6 months out, she received her influenza and COVID vaccines and then came in a month later for follow-up and what her complaint was that her eyes were a little bit dry, felt like there was a little graininess to when she closed her eyes, and her mouth was a bit dry, realized she had to drink more fluids when she ate meals. And then her biggest complaint was that her whole body felt stiff. And this manifested as I have trouble taking off my bra when I reached around. I have trouble reaching down to put on my socks and put on my shoes and my whole body just feels stiff.
When we did a comprehensive physical exam, which is crucial to an evaluation of chronic GVHD, certainly the oral exam showed a little bit of a reticular pattern on her bilateral buccal mucosa. No frank ulcerations or anything else. Her eyes actually appeared fine. They did not appear irritated at all, just felt dry. And then in terms of her skin exam, there was no rash. There was no hide bound feeling, but certainly her range of motion was somewhat limited in several joints when she bent down compared to before.
I certainly felt she had the new onset of classic chronic GVHD that involved the eyes, the mouth, and also her fascia. It wasn't true sclerodermas disease of the skin, just fascial disease that was limiting her quality of life and flexibility and range of motion.
It's interesting, we wonder if it was triggered by the influenza and COVID vaccinations as we've seen this before. There's no way to say, there's no test to show that, but we definitely have seen that before where non-specific inflammation from either vaccinations or an infection can then lead to the development or worsening of established chronic GVHD several weeks later.
So given the fascial disease, we did feel that she merited systemic therapy. I discussed with her local physician and we started her on half a milligram per kilogram of prednisone. I mean, unfortunately, systemic steroids do remain standard first-line therapy. I think all of us in the field would like to see something different because of the toxicities of steroids, especially in older patients with comorbidities. But for now it remains a standard therapy. So that is what we started.
These days, I think that I have a very short leash to move on to something else because we now have several approved agents for the treatment of steroid-refractory chronic GVHD, or second-, third-, and subsequent-line therapy. We have 4 agents that are approved that you all know, ibrutinib, ruxolitinib, belumosudil, and most recently axatilimab. And there are other options that are viable as well, such as photopheresis. And so these days compared to where we were before, say a decade ago, I think we have a much shorter leash for steroids because of the harm they cause.
And so, I put people on steroids and then 2 weeks later I have a very thorough assessment to figure out if steroids are a hurting, helping, or doing nothing. And so, I think you have to figure that out because we do know steroids are harmful, but we also know they have a response rate. You can look at all the trials in chronic GVHD recently. Steroids do have a response rate, but you have to figure that out and calculate sort of this cost-benefit calculation as to what you want to do.
We saw her after 2 weeks, she basically felt the same. I mean her appetite was better, just being on steroids, didn't sleep very well on steroids. So, at that 2-week assessment, which is early compared to the traditional sort of thoughts, I added ruxolitinib as second-line therapy. That's become our standard second-line therapy based on years of use, based on the REACH-3 trial, based on our experience and so forth.
I added ruxolitinib at 10 milligrams twice a day, standard dose, to see if it could help. I was worried that steroids were not going to help the myofascial disease, which is a very difficult phenotype to treat. Certainly, added the topical therapy when we started steroids for the eyes and the mouth in terms of drops as well as steroid rinses for the mouth.
With ruxolitinib therapy, I tend to add it, and I want patients to wait at least 3 months. This disease does not happen overnight. It takes a long time to develop these symptoms. And so, if you have an effective therapy, it will take a long time to reverse those symptoms as well. And so, with ruxolitinib, we were able to continue on therapy. Certainly, it did not get worse. At that point, I would see her once a month for follow-up, but in between, every 2 weeks, she would see her local physician and we would talk as well to make sure she was doing okay.
Each time I would see her, we would certainly look at the areas that were involved, the eyes, the mouth as well as her myofascial disease, but also really do a comprehensive review of systems to figure out if she was developing any new organs as well. After 3 months of therapy, which is the minimum, I would give a chance for one of these newer therapies to try and work and try and assess a response. She had had significant improvement in her eyes and her mouth, and that might've been from the topical therapy also, but also significant improvement in her myofascial disease. She felt more flexible, was able to do more things and felt things were moving in the right direction. However, certainly did not have a complete response and certainly did not feel she was back to her normal or desired quality of life.
And so, this gets to a couple of things, a couple of concepts. One, I added ruxolitinib after 2 weeks of steroids, and that's normal for us now because we don't wait for conventional true steroid-refractory disease because of the toll of steroids. The motivation to add ruxolitinib these days can also be to improve upon a partial response or the ability to taper steroids. So by that 3-month timeframe on ruxolitinib, I had taken her half milligram per kilogram of prednisone and was down to already 5 milligrams of prednisone because it's harmful and we wanted to get it off.
On ruxolitnib. She did have certainly a partial response by NIH criteria, which is the consensus criteria to grade and assess response in chronic GVHD. But at that conversation, she did not feel that we had achieved a quality of life that was acceptable to her to stop at. I said, let's give it a little bit of time. I'll see you back in a month and we'll see how you are. We waited one more month, so now 4 months on ruxolitinib. And from month 3 to 4, she did not feel she had any improvement at all. Certainly, didn't take a step backwards, and so we sort of had hit this plateau in response for chronic GVHD.
And sometimes you're able to find that in 4 months. Sometimes it takes 12 months where you stopped improving from the therapy. Remember, this is a chronic disease that's very slow growing, and so it's very slow in re-progressing as well. And so, at that 4-month period, we felt we had a plateau. We have a conversation with patients, and we talk about where you are, what's your quality of life or what responses you've achieved. We look at what their goals are in terms of what they do in life and so forth, what's acceptable and what's not. And we had joint decision making to decide, well, let's try another therapy to see if we can get a better response.
In the past when we didn't have any of these therapies and what we have was sort of systemic immunosuppression, which was far more toxic, it was less of a joint decision-making model. We were so scared of risk, so scared of infections that this response that we had achieved already, we would've framed it differently for patients because we didn't have effective therapies to go on beyond this. Now we're able to have a discussion about what your quality of life is, what you're trying to achieve, and make a joint decision of should we try third-line therapy or not?
And so, what are the options for third-line therapy? I'd mentioned the 4 approved agents that we have. She's now on tapering steroids, almost off, and ruxolitinib. We have ibrutinib, belumosudil, and axatilimab. Ibrutinib was the first approved, but we found it to be not as efficacious and certainly the most toxic out of all those drugs. And so we and others do not routinely use ibrutinib for the therapy for chronic GVHD anymore. And so the choices really come down to belumosudil or axatilimab or discussion around photopheresis.
Photopheresis requires so much investment of time from the patient and time at the center. She lives in Maine, several hours away, so that was not going to be a practical option. So it was really going to belumosudil, which is an oral ROCK1/ROCK2 inhibitor or axatilimab, which is the most recently approved monoclonal antibody against CSF1R. And we talked about what we knew from each. We went over the published data, which admittedly look very similar. They've never been compared head-to-head. We don't have a randomized trial in this setting to guide us.
Belumosudil is an oral agent. Axatilimab is an intravenous infusion that's done every 2 weeks. She felt that both are thought to be somewhat directed against the fibrosis cascade and so forth. Theoretically, there may be some overlap in the mechanisms behind belumosudil and ruxolitinib, but that really hasn't played out or been proven. We had a long conversation about she actually did not want to take another pill, did not want to add to her pill burden, and felt she would be okay coming every 2 weeks, even down to Boston to see me and receive an infusion of axatilimab.
And then she liked how it was an IV infusion, then she'd be done and wouldn't have to deal with more pills at home. And so, we started axatilimab. We've been able to give it since early March at our center, which is when we had access to it. She's tolerated it just fine without any infusion reactions whatsoever. And we've continued the ruxolitinib because she was getting benefit from it but have tapered it down from 10 BID to 5 milligrams twice a day. And with axatilimab, she's received about 4 or 5 infusions now. We've definitely noticed the continued improvement of her flexibility, a regression of the fascial disease even beyond what she had achieved before, even with lowering of the ruxolitinib and now being off prednisone therapy.
And so really a good illustration of how we've been able to get away from prolonged courses of high-dose systemic steroids, how we've been able to capture a response from myofascial disease, which is typically a very difficult to treat phenotype of chronic GVHD and make use of newer therapies such as ruxolitinib and axatilimab.
And so, we're continuing both of those for now, and we'll try and get as much benefit as we can. But the goal is not to be on therapy forever. And so, in the long run, we'll hopefully figure out when we've achieved either a complete response, which is rare in chronic GVHD or a plateau that's acceptable for her and figure out how to taper off therapy. That was a long-winded answer to this case, but I hope that it's been informative and I thank you all for joining me today. Have a good afternoon.
