Shifting their focus to chronic graft-versus-host disease, experts review a patient scenario and discuss the challenges in early intervention.
Nelson Chao, MD: We’re going to switch gears now and talk about chronic graft-versus-host disease. This is a 60-year-old man who underwent myeloablative conditioning and then a marginally-related donor transplant for ML [mucolipidosis]. His GVHD [graft-vs-host disease] prophylaxis was the standard tacro [tacrolimus]/methotrexate. The donor is CMV [cytomegalovirus] positive, [a] 43-year-old woman with 2 children. Initial transplant course was uncomplicated, and the patient engrafted by day 20. On day 27, the patient developed a maculopapular rash on his face, chest, and arms. He received glucocorticoids. The rash resolved. Nine months after transplant, he presents with very dry eyes with a foreign body sensation. It’s treated with topical agents, but the symptoms persisted. Three months later, he has muscle and joint pain, which limits his ADLs [activities of daily living], and he’s treated with prednisone and the symptoms improved. Nineteen months after transplant, he shows up with sclerodermatitis changes, decreased range of motion, decrease FCD [Focal Cortical Dysplasia] 1, DOCL, and PFTs, without shortness of breath. So 2 questions: What are the challenges to early intervention in chronic GVHD? And what staging systems do you use when reviewing such a patient as this?
Corey Cutler, MD, MPH, FRCPC: Well, you’ve just described a case where one would have guessed 100% that this patient was going to get chronic GVHD. You’ve listed almost all of the major risk factors here. You’ve done a sex mismatch transplant from [a] CMV-positive donor. You describe early acute graft-versus-host disease, which traditionally was one of the major risk factors for the development of chronic graft-versus-host disease. The patient received a standard GVHD prevention regimen, but one that we know is probably associated with higher rates of chronic GVHD in the long term. The challenge here is being able to identify the patient who, number 1, is going to develop chronic GVHD. We are very behind in the biomarker field in identifying these patients. Then, deciding on whether there was a role for preemptive type therapy, once the patient developed what was clearly ocular graft-versus-host disease while they were treated topically for it.
At that point, a systemic intervention may have prevented some of the multi-organ or multi-system involvement later on with myofascial disease and eventually, with sclerodermatous disease. So I think there are a number of challenges here. The greatest is that our therapies for chronic GVHD are not wonderful. In the frontline, just as in acute GVHD, corticosteroids do remain the mainstay either with a calcineurin inhibitor or increasingly with an mTOR [Mechanistic target of rapamycin] inhibitor based on the CTN [cardiac troponin] or later 1 trial. This is also like the first case, a very clear case of chronic GVHD. This is a case that we could easily stage, using the chronic GVHD staging system. One looks at the number of organs that are involved and the severity of each of those organs’ involvements, then come up with an overall score of mild, moderate, and severe. When this patient only had ocular disease, they most likely had mild disease. But once they developed a second organ with impairment of their ADLs and quality of life, that would then qualify as moderate to severe disease, and particularly, when they developed sclerodermatous change. This change would definitely fall into the moderate to severe category. So again, this is sort of a prototypic case at all levels of chronic GVHD that we see far too regularly.
Nelson Chao, MD:Any thoughts on how things could have been done differently for this patient?
Corey Cutler, MD, MPH, FRCPC: These long gaps and the fog.
Kerry King Minor, MSN, ANP-BC: Like Dr Cutler said, this patient had clear risk factors. So 1, I would not recommend that much time in between each follow-up. The only time I would do that is if I have a patient I clearly trust and a local provider that I clearly trust that has maybe some experience with transplant. I still would try to keep them a little bit closer under our eye. When they develop the ocular symptoms and they didn’t resolve with topicals, it definitely would have a much shorter interval for follow-ups with this patient. I think one of the challenges that I’ve come across is hesitancy of patients. I’ve often heard patients say, “Well, I planned for the first 100 days, but I didn’t realize I was going to have follow-up for years,” and they get back home and get comfortable. And even when they start to have some changes, they are either in denial or just don’t want to reach out or come back. So it’s hard when they’re back at home in other states to continue good, close follow-ups like these patients need.
Nelson Chao, MD: So I’m going to push back a little bit on what Dr Cutler said. What do you think mechanistically would make a difference treating early versus late in somebody like this? Let’s say, she came in with dry eyes and you gave a topical, would you also start something else at that point? You think it would have prevented much of this?
Corey Cutler, MD, MPH, FRCPC: I don’t think we know the answer to that. I think that is actually a great topic for a clinical trial. So this is someone who is at risk of developing multisystem chronic GVHD at the time they develop the ocular disease. And so, designing trials to begin early intervention at that time with systemic immunosuppression need to be done. The question is, what agent would you use at that point? Because not everyone who develops ocular GVHD is destined to develop multisystem systemic disease. And I think we could do a lot of harm if we put everybody who developed eye disease only on systemic corticosteroids for months at a time, which could potentially do more harm than good. The introduction of our newer agents, which we’ll get to shortly, might be an opportunity to use somewhat less toxic interventions in this setting. But I don’t think we should be doing this outside of the auspices of a clinical trial at this point, because we don’t know that we’ll actually have an impacting outcome.
Transcript edited for clarity.