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 the 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 everyone. Mitch Horwitz here. I'm the Director of Adult Blood and Marrow Transplantation at Duke University in Durham, North Carolina.
Dr. Chen:
In this installment, we will be discussing identification of chronic graft-vs-host disease, the importance of early detection, and tools that can be used to facilitate the diagnosis of chronic graft-vs-host disease. Let's get to the case.
The first case involves a 55-year-old male patient with FLT3-ITD mutated acute myeloid leukemia in first complete remission, who then undergoes a myeloablative, unrelated donor, peripheral blood stem cell transplantation. Conditioning was given with myeloablative busulfan accompanied with fludarabine, and graft-vs-host disease prevention was with tacrolimus and methotrexate.
During his transplant course, he had the usual toxicities including febrile neutropenia, mucositis and even typhlitis. But he did recover, engrafted his cells, which were of donor origin and was able to be discharged from the hospital in the expected time. Around day 30, because his AML had the FLT3-ITD mutation, his providers chose to start maintenance gilteritinib, a FLT3 inhibitor, at that point in time to prevent disease relapse. Around day 40, in transplant clinic, he presented with a new stage 3 skin rash consistent with acute graft-vs-host disease. This was managed with systemic prednisone at a dose of about 1 mg/kg per day, and he had a great response achieving resolution of his rash.
There was no GI or liver involvement from acute graft-vs-host disease and the prednisone was tapered after the rash responded and was able to be discontinued by day 100 after transplantation. About three weeks later, around day 120, his tacrolimus was started to taper in efforts to try and eventually discontinue immunosuppression. However, around day 200, he was able to complete his tacrolimus taper without any toxicities. At that point, his transplant doctor handed over his primary follow-up to his local oncologist as the patient lived far away from the primary transplant center. While there were alternating visits, most of the follow-up was done with his primary oncologist out in the community.
Around day 300, so that's about 10 months out from his original transplant, he showed up for follow-up at the transplant center. At that point, he complained of dry and irritated eyes. They were a bit injected on exam. He said he constantly felt like there was a grain of sand in his eyes. His mouth was dry and there were sensitivities to acidic or spicy foods. Upon examination, his skin had a faint, yet evidenced, scaly spotty rash that when upon palpation felt a bit like shark skin and there were some open areas on the back, which were quite painful.
So let's stop right there, okay? And Mitch, I'd like to ask you, what do you think the risk factors in this case are for this patient to develop chronic graft-vs-host disease?
Dr. Horwitz:
Yeah, that's a good question because as you know, Yi-Bin, chronic graft-vs-host disease is a clinical diagnosis. We don't have yet and we're working on it, but we don't have yet, tests that we can perform that confirm the diagnosis. So we have to carefully consider the risk factors for a patient who's at risk for graft-vs-host disease. And when I look at this case, there are a number of risk factors.
First, we have a male patient with a female donor, and we know that when there's a sex mismatch in the female to male direction, there's a slightly increased risk of chronic graft-vs-host disease. We also know that when a patient receives a myeloablative conditioning regimen, a regimen that's very high intensity, that also puts the patient at a slightly higher risk. The patient received a matched unrelated donor transplant. Now it's a matched donor, but with unrelated donor transplants, again compared to someone getting a matched sibling donor, slightly increased risk of chronic graft-vs-host disease.
And finally, when I look at this case and see that this patient had developed acute graft-vs-host disease, something that we see quite commonly, that is another risk factor. So while this patient could possibly have gone home and continued the tacrolimus taper without evidence of graft-vs-host disease, the risk factors were there, and it doesn't surprise me that he's presenting now with a relatively mild form of chronic GVHD, yet one that does need to be addressed.
Dr. Chen:
Yeah, I agree. I think we as transplant providers accept a certain risk of graft-vs-host disease when we do these transplants. So there's certain decisions that we make here that do get at the risk factors you're talking about. Looking through, it's probably not that his transplant doctor chose a female donor. It's probably that was the best available donor. The one other thing we should point out here is a peripheral blood stem cell graft was used as well, instead of bone marrow, which we try not to do in the setting of myeloablative unrelated donor transplant, but sometimes we have no choice. Especially in the last 2 years with pandemic dynamics, it was very difficult to receive fresh bone marrow from an unrelated donor.
And so there's these risks. I think we in the community have accepted that maybe we should have a little bit of chronic graft-vs-host disease because it does help what we believe to be the graft-vs-leukemia effect. But you and I both know, we can't just dial in a little bit, and sometimes when we ask for a little bit we get a little bit of a lot or even too much.
Dr. Horwitz:
Yeah.
Dr. Chen:
You characterize this presentation as mild, which I wouldn't disagree with. When you see a patient who presents like this, now 10 months out, what expectations do you give that patient in terms of how to move forward here, and what we're trying to achieve? And will his organs ever get back to normal?
Dr. Horwitz:
I think that whether you're a managing oncologist without transplant specialty or a transplant physician, I think we need to be reassuring to the patient when they present with these symptoms. Now, this patient did have acute graft-vs-host disease, so he's already experienced that complication. But nonetheless, they can be very anxious about complications and particularly graft-vs-host disease, knowing that that is the one thing that they need to be on the lookout for.
So I would be reassuring. I would also emphasize the point you just made, which is that when we do see what we call alloreactivity, we see a graft-vs-host disease, we also expect that there is a graft-vs-cancer effect as well that may work in their favor. Nonetheless, although this would be considered mild or maybe moderate given the number of organs involved, I think that the eyes, the mouth and the skin probably do demand a multidisciplinary approach to management, particularly the eyes. Because when someone has these types of symptoms, they are actually at quite a high risk for developing corneal abrasions and other very uncomfortable and sometimes longstanding problems with the eyes.
So I would be reassuring, I would tell them that this is likely to respond to therapy, but that if possible, they should return to the transplant center if specialty care for, particularly the eyes, but even oral GVHD and skin, if it can't be managed by a specialist in their area.
Dr. Chen:
Yeah, I agree. I think I try to be reassuring with patients who present like this. I also fear that some irreversible organ damage has already been done that I can't figure out. I don't think we ever know what percentage of the symptoms, or the damage shall we say, is reversible or is it just that we haven't had great therapy, so we haven't seen that reversibility?
I think there's also a belief in the field, never truly proven with prospective trials, but it's hard to prove. But there's a strong belief in the field, and I would agree with it, that perhaps earlier detection and the implementation of earlier treatment perhaps can prevent morbidity late.
So here, at around 6 months, the immunosuppression was tapered off, and the patient had no signs of chronic graft-vs-host disease, was in remission. Primary follow-up was returned to the local oncologist for good reason. I think the patient has a relationship with the local oncologist and lives quite far away from the transplant center. But then 3 months later, they present with chronic graft-vs-host disease that we wonder, perhaps we could have intervened earlier. How do you think we can get better at facilitating early diagnosis? Is it on us, is it on the patient? Is it on education? What do you think we should do?
Dr. Horwitz:
Yeah, I think it's on all those, Yi-Bin. As I mentioned before, this is a clinical diagnosis, so we really rely on the patient to bring early symptoms to our attention, whether it be the transplant physician or the managing oncologist, early. And as much as we inform and educate, some patients are quite stoic, and maybe their local managing physician is quite a distance or there's other barriers. But for sure, I think, before they leave our center, we need to do as good a job as we can, and sometimes we don't do this as well as we can, to inform patients of what they might expect, particularly as they continue with tacrolimus or an immunosuppression taper, which often takes place after they leave the transplant center. In fact, more times than not, it does.
So educating the patients on the symptoms, making sure that they have someone locally. It doesn't have to be an oncologist, it can be a primary care doctor or an advanced practice provider, that they can reach out to, to say, "I've just been having to put eyedrops in a little more frequently than I usually do." Or, "I'm having trouble eating a sandwich without drinking a lot of water to get it down."
Those are the early signs that might have tipped someone off that this was happening. And as you point out, when you start to see patients with dry eyes or dry mouth, this keratoconjunctivitis sicca, sometimes that is irreversible when there's damage to the lacrimal glands or the salivary glands. It's not life-threatening for sure, but it is life-altering, and it would be nice to catch that as soon as possible before the end organ damage occurs.
Dr. Chen:
I've wondered over the last few years how we can improve this. I think when I first joined faculty, which is now about 15 years ago, and started to consent patients for transplant, I'm sure you have the same consent visit where patients sign a bunch of forms about a week or two before admission. I personally would try to comprehensively go over everything, like everything, including chronic graft-vs-host disease. And what I quickly realized was that patients and their families were just fixated on the transplant admission or those first 4 weeks of what was going to happen and would the transplant take? And even though I talked about this risk, or this risk, I just think people, and I'd be the same way, people are unable to comprehend that and grapple it. And then certainly, they're not going to hold onto that for the long run, right?
Dr. Horwitz:
Yeah.
Dr. Chen:
I think it's on us to a certain extent to provide continued education through the transplant course, and we need to empower our patients to tell us about these things. You can envision at day 200 when the patient was sort of "discharged" back to their private, not private, but their community oncologist, that they may have felt that there were no more risks. And we have to be careful not to provide that false sense of reassurance. Sometimes patients don't want to tell us. They don't want to be sick anymore.
Dr. Horwitz:
Yeah.
Dr. Chen:
They feel well and they don't want to believe that something is happening. I think a lot of this, it has to be on encouraging communication and getting to the point of being comfortable talking about all this and overcoming those barriers. But yeah, I think it's a challenge. I think it's a challenge that you and I both face on a daily basis as we see these patients. And this patient is based on a true story of a patient of mine. You just wonder if perhaps we had seen the patient earlier, maybe the eyes and the mouth would not have progressed to where they were and where they are now.
Dr. Horwitz:
We do have new technologies that are at our disposal, that I think can be utilized even more effectively with just a video visit or having the patient who is somewhat tech savvy and can send a picture through the portal of their skin or just message their transplant provider about new symptoms. We need to encourage more use of that. But of course, we do have some patients who just have trouble with those modalities, and we have to encourage them to call or use other techniques that are easier for them to communicate.
Dr. Chen:
So to summarize, I think there's not one thing that we need to do to improve upon this. I think there's multiple facets that we can address to improve on earlier detection and potentially earlier intervention for chronic graft-vs-host disease, ultimately to improve outcomes.
The key clinical takeaways from this case would be that patient engagement in the monitoring and reporting of symptoms of chronic graft-vs-host disease is essential, and thinking about ways to improve and facilitate that is a huge priority for the community. And then comprehensive evaluation with a transplant provider is needed even in the long run for follow-up, how ever we achieve that, be it in person, be it virtually, or whichever way we achieve that. I think comprehensive evaluation is needed so we can detect those subtle and emerging symptoms to help patients achieve the outcomes we'd like them to achieve.
So 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.
