Corey S. Cutler, MD, MPH, FRCPC

 We touched a little on how to manage treatment-induced damage. Dr Cutler, what’s the long-term prognosis of this patient?

 It turns out that the long-term prognosis is not bad. There definitely is mortality associated with chronic GVHD [graft-vs-host disease]. I worry more about the morbidity that’s associated with chronic GVHD rather than the mortality. We would probably quote this person [as having an increase in] annualized mortality of only a few percentage points per year. That number doesn’t go away. We know that studies of BMT [bone marrow transplant] survivors suggest annualized mortality ratios that are much higher than age-matched controls for up to 20 years beyond their transplant. Even if you go out to 15-plus years, the standardized mortality ratio for this person is 2 1/2-fold higher than it is for an age-matched control, based on some of the BMT survivors studies out of the City of Hope center. So as was just mentioned, one has to be very careful in taking care of the other potential long-term sequelae of both the GVHD itself, the transplant itself, and the therapeutics we use to treat chronic GVHD, all of which contribute to the long-term morbidity and mortality of this patient.

 I couldn’t agree more. I think this is where a partnership with their local provider is really important. Many times patients return to their home and don’t want to come back, and therefore come back infrequently. And so, I think knowing where the potential damage could be, or could be developing, is really important. We didn’t talk too much about secondary malignancies, but this is clearly a significant morbidity and potential mortality for these patients, where the cumulative incidence of secondary malignancies does go up significantly. This is not because they have chronic GVHD, but is rather from all the prior regimens that they had. I think these are really important points. I’m going to leave the last word for you, Dr Cutler. Can you share the summary of the field, where you are the guru of chronic GVHD? Where do you see this field going, and what can we expect next?

 I think it’s quite an exciting time to be working in the field of chronic GVHD, with 3 drugs approved in the last 5 years and likely more to come in the next few years. I think this is exciting for our patients, and it’s going to change long-term outcomes for sure. Where we need to go is a much more personalized approach to chronic GVHD therapy, finally deciphering which patients have a dominant biologic pathway driving that GVHD and targeting that pathway initially, rather than the guesswork that we currently do to choose appropriate agents. I think further prophylactic strategies or even preemptive strategies against chronic GVHD are really important, and probably are going to markedly diminish the long-term impact of chronic GVHD, both in terms of severity and incidence. And for that reason, I think transplant in the long term is going to have improved outcomes as chronic GVHD becomes less of a burden, both in terms of morbidity and mortality. So, I’m pretty bullish on the field at the moment.

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Closing out their discussion on graft-versus-host disease, participants reflect on patient prognoses and the future directions of care. 

Chronic GVHD: Prognoses and Future Directions in Care 

I want to briefly touch on some of this treatment-induced damage. This is part of the big problem we have in some of these patients and dealing with all the damage that we’ve caused. Partly, it’s their chronic graft-vs-host disease [GVHD]. I was wondering if you could go through some of these that you see frequently. Additionally, how, in a multidisciplinary way, can we recognize them quickly and address some of them?

 Unfortunately, we see a lot of these. I can’t stress enough the importance of continued follow-up. With more patients surviving transplants, this allows us to see the aftermath of transplants and the treatments they’ve seen. I’ve seen it enough to prepare these patients, as part of my initial presentation, that you’ll be with us for a while. We’ll continue to follow up with you. The importance of the survivorship clinic is that we get past the acute concerns of their cancer or their underlying diagnosis and start to shift our view more to managing these items.

Close follow-up is huge. The minute we have any concern of any of these items, we have them plugged in with some of the other specialists. But to be prophylactic or preventive, we need to make sure we’re following up on their bone health. Checking their vitamin D when they come back for a follow-up is important. We tell these patients, “Don’t go in the sun because it can cause GVHD.” But they need to be reminded of the importance of replacing that with a vitamin D supplement. This is to protect their bones. If they’ve been on a long-term steroid and tapered off, have that in the back of your brain and follow up closely with them for adrenal insufficiency. For most of them, if they’ve had issues with steroid-induced diabetes, we just go ahead. Our main practice is to plug them in with an endocrine group that very closely monitors them for the duration.

Another preventive would be cataracts. I’d always recommend, at least by a year, that these patients need to be getting back in for good eye exams. [They also need to] see a dermatologist and make that an annual or every-6-month practice. Getting back in with their PCP [primary care provider] is a learning point for them or a reminder, even if they’ve heard it before, of how important these follow-ups are. Making sure someone is checking their cholesterol, checking their hemoglobin A1C [glycated hemoglobin], and doing their DEXA [dual-energy x-ray absorptiometry] scans is important post-transplant.

A brief discussion on the risk of treatment-induced damage when managing patients with chronic graft-versus-host disease.

Scenario 2: Treatment-Induced Damage in Chronic GVHD

Going over the data in the guidelines, what treatment would you select for this patient at this time? Dr Cutler?

 Going back to the case, this is someone who did have a response to corticosteroids when they had myofascial-type symptoms but now has a real sclerodermatous disease. It would be tricky to call this failure of 2 or more lines of therapy. I’d like to use belumosudil because of the antifibrotic properties that drug has, but from a regulatory point of view, ruxolitinib would probably be my choice. The reasons why I’d choose ruxolitinib over ibrutinib in this scenario is that this patient wouldn’t qualify for the ibrutinib trial as it was designed. In that initial 42-person study, patients had to have the inflammatory manifestations of chronic GVHD [graft-vs-host disease], such as an erythematous mouth or an erythematous skin rash, and this patient has neither of those. So I’d choose ruxolitinib or belumosudil at this point. Of course, if there were a clinical trial available, that would be my first choice, particularly if a trial of axatilimab, for example, was available. There are other options to use here. But staying within the approved agents list, I’d switch to ruxolitinib or belumosudil if I could get it.

Dr Minor, what are some of the adverse events that you see in these patients that would guide you 1 way or the other?

 One thing I always take into consideration is what they’ve tolerated in the past. I don’t want to leave people on corticosteroids for long periods of time, but some people do OK. Many have glucose levels over 300 mg/dL, and they just melt in front of you. Knowing about a patient and how they responded is important. Similarly, before we had some of these other steroid-sparing agents, we were just slapping things on them, and we might go back to a calcineurin inhibitor. If I knew someone’s blood pressure shot through the roof or they had kidney issues at this point, that would impact whether I’d be able to use that agent again. But now the thought is, we some other agents that we can stun them with, initially with corticosteroids, and then put them on a steroid-sparing agent, which will get them off the steroids much faster. In doing that, you can hopefully avoid some of these adverse events that they may have seen in the past when the previous players of GVHD had presented themselves.

I think that’s true. It’s encouraging that we’re moving to a phase where we have a more standardized approach to treat these patients after steroids because it’s been so center-specific and boutique-like that it’s been difficult to compare data. One of the better things we’ve done with the BMT CTN [Blood and Marrow Transplant Clinical Trials Network], as well as some of these larger pharma studies, is recruit patients to answer some of these important questions. From what I’ve been hearing, the nice thing about belumosudil is that it’s well-tolerated, and there were very good responses. Ruxolitinib works. The tolerability is a little more difficult because of the known toxicities to the marrow. Some patients don’t have great counts. One problem with chronic GVHD has been the impact on the marrow. Sometimes they end up with very low platelet count studies. And it may be very difficult to use some of these drugs because of the heme toxicity.

Having reviewed approved treatment options for steroid-refractory, chronic GVHD, experts discuss how they would address this patient scenario.

Scenario 2: Selecting Therapy for Steroid-Refractory GVHD

Let’s go on to the third drug, which is belumosudil. This drug was approved in July 2021 for patients and pediatric patients 12 years and older with chronic GVHD [graft-vs-host disease] after failure of at least 2 prior lines of systemic therapy. I’m going to turn this over to Dr Cutler, who’s the lead investigator of this trial.

 Thanks, Dr Chao. This was the second trial performed using this novel compound. Just of note, this is the first compound developed and specifically approved in chronic GVHD. Based on a phase 1 dose-escalation trial that enrolled just under 60 patients, we chose 2 potential recommended doses for a randomized trial in the ROCKstar study. In this trial, we enrolled 132 subjects and randomized them between 2 dosages of belumosudil: 200 mg once daily or 200 mg twice daily. Similar to the design of the REACH3 trial, we included some stratification factors, which included the prior use of Ibrutinib. At that time, it was the only FDA-approved compound available. We stratified by moderate to severe chronic graft-vs-host disease. This was a real-world trial population. These were sick patients, more than 2 years after the onset of their chronic GVHD, and most had multiple origins and had 3 or more lines of therapy. This was a sick advanced group of patients with chronic GVHD. What’s shown is the response rates. The overall response rates for the 2 arms were approximately 75%. We did not notice differences between the 200-mg daily and the 200-mg twice-daily dosing in this study.

What was very important as well was that we noticed significant responses that were no different from the overall response rate in patients who are previously exposed to ibrutinib or ruxolitinib. This wasn’t part of the original design, we did analyze it at the end. It didn’t matter if patients had previously had 3, 4, or more lines of therapy. The response rates were all the same, no matter how we cut the data. On the basis of this study, the FDA granted a full approval to belumosudil for the management of patients with 2 or more lines of prior therapy in chronic graft-vs-host disease.

We also looked at things like quality of life and organ-specific responses. We were able to demonstrate very nice broad organ responses across the board, including responses in the lung, which we had not previously seen. The drug was very safe. The adverse-effect profile is seen on these slides. The standard adverse effects that one would expect in a trial of patients with advanced chronic GVHD were seen. But the incidence of grade 3 or higher adverse effects that were found commonly were only pneumonia, hypertension, and hyperglycemia—things also associated with chronic corticosteroid use.

One interesting point you brought up is to see the responses in the lung. That’s probably 1 of the more encouraging aspects. Up to this point, it’s been very difficult to see responses in the lung. Other drugs are out there, including axatilimab, which is a monoclonal antibody that targets the CSF1R receptor protein in monocytes and macrophages. There are increasing data to suggest that a lot of the inflammatory and profibrotic responses we see in chronic graft-vs-host disease may be from monocytes and macrophages. This might be a quite interesting way to have a novel mechanism of action that’s targeting a cell that’s different from what we’ve been focused on in the past, which had been T cells or B cells. For phase 1/2 open-label dose escalations studies, 40 patients had 2 or more prior lines of therapy, including ibrutinib, ruxolitinib, and belumosudil. The median involved 4 organs. Overall responses have been 66% to 70%, and 4 of 13 patients had responses to the lung. Median time to the first response was 0.9 month. It was well tolerated overall, which is something else to keep in mind.

There are other clinical trials. There’s a lot of interest in the potential of combination therapies. These are some of the trials that are recruiting. Trials using ruxolitinib and belumosudil with 2 mechanisms of action, for example, may be quite interesting with patients who have severe chronic graft-vs-host disease.

Considerations for belumosudil and axatilimab as treatment options for steroid-refractory chronic graft-versus-host disease.

Scenario 2: Belumosudil and Axatilimab as Treatment Options in cGVHD 

Let’s talk about the treatment options. In general, if it’s mild [graft-vs-host disease], with dry eyes or topical skin changes, supportive treatment is usually enough. If it’s moderate to severe, systemic treatments should be used, like steroids. Based on the NIH [National Institutes of Health] criteria, one waits for response when asked to monitor for infections. Keep in mind, you’re adding immunosuppressants to a patient who’s probably immunosuppressed already by virtue that the patient developed chronic GVHD [graft-vs-host disease]. We talked a little about this earlier, but supportive care is really important in patients: physical therapy, occupational therapy, mental health support, and financial support.

The guidelines from NCCN [National Comprehensive Cancer Network] for steroid-refractory GVHD are listed here. Clinical trials are still No. 1, although there are 4 FDA-approved drugs: ruxolitinib, ibrutinib, and belumosudil. Imatinib was the first to be approved. This was based on a very small study of 38 patients, I believe.

 Forty-two patients. As you can see, there was a reasonable CR [complete response] rate, with an overall response of 69%. Looking at the median corticosteroid dose, the treating physicians felt comfortable enough to be tapering their steroids in terms of the people who responded. This was approved in 2018. The FDA approved ruxolitinib for chronic GVHD in September 2021. This was for patients who failed 1 or 2 lines of therapy—adult and pediatric patients 12 years or older.

I want to go over the phase 3 REACH3 study. This was a large, randomized study of 329 patients who were stratified by their chronic GVHD grade. They had a lack of response and progressive disease after 1 mg/kg for 1 week, or 0.5 mg/kg for 4 weeks, or an increase of the prednisone dose of more than 0.25 mg/kg after 2 unsuccessful attempts to taper. They had to have myeloid and platelet engraftment. They’re randomized into the ruxolitinib, with steroids plus or minus the calcineurin inhibitor, or the best alternative therapy. The first primary end point was at week 24, looking at overall responses. The secondary end point looked at failure-free survival substitute. There was a similar design for the GVHD. It was ruxolitinib compared with the best alternative therapy. Those were selected by the investigators and included ECP [extracorporeal photopheresis], low-dose methotrexate, MMF, mTOR inhibitors, infliximab, rituximab, pentostatin, and imatinib.

There was an extension period up to week 156. These data show that about half the patients had an overall response by week 24. Overall responses were great. Complete responses were relatively few. The best overall response ended up being about 76% for ruxolitinib and about 60% for the best alternative therapy, so it looked like all organs responded. The patients who crossed over—there were 61—also had a response similar to what one saw with the ruxolitinib up front.

This [chart] is for failure-free survival. You can see the ruxolitinib curve, at a robust failure-free survival, compared with the control arm with a hazard ratio of 0.37. The duration response was also better with ruxolitinib compared with the control, with a duration of response not reached on a ruxolitinib mark.

We didn’t talk about this in the acute setting, but ruxolitinib clearly has adverse events. Most of the adverse events are hematologic, with an increase in anemia, thrombocytopenia, neutropenia. Not surprisingly, these are the adverse effects of the drug. Outside that, it wasn’t terribly different in many of the other adverse effects that it had when compared with the control.

A review of treatment options approved for steroid-refractory chronic graft-versus-host disease starting with ibrutinib and ruxolitinib. 

Scenario 2: Ibrutinib and Ruxolitinib as Treatment Options in cGVHD

 So what percentage of patients with acute GVHD progressed to chronic, Dr Cutler?

 It’s variable. You know, we used to say that acute GVHD [graft-versus-host disease] was the most important risk factor for chronic GVHD. I don’t think that’s necessarily true any longer. And so, acute GVHD is certainly not a prerequisite for chronic GVHD. The 2 processes might arise out of the same immunologic phenomena, but 1 doesn’t necessarily lead to the other. And certainly, there are many patients who develop no clinical acute graft-versus-host disease, but who develop chronic GVHD. So I do think about them as entirely separate entities, but still recognize that the development of acute GVHD is a risk factor for chronic GVHD.

 I would agree with that. Although I think if you have acute, the chances you’re going to get chronic are clearly much higher than if you’ve not had acute. You know, they’re clearly in over chronic, which we see frequently. How is a management of chronic GVHD different from acute?

 Well, for chronic, it can include a wide range of organs versus with acute just being mostly liver, gut, and skin. So, with that, I feel like we find ourselves pulling from several different specialists to make it more of a multidisciplinary approach to these patients. Like for this patient with the drop in the FEV [forced expiratory volume] 1, are we going ahead and reaching out to our pulmonary colleagues with the sclerodermatous changes? Are we reaching out to our derm [dermatology] colleagues for thoughts on if there’s a role for light therapy, or ophthalmologists for something other than just the basic usual topicals that we may use? And then, on top of that, these are not managements that I feel like are going to go away as quick as the acute side of things. So I’m usually getting social work and our pharmacy techs involved to help with patient assistance. Because these patients will be on more than likely their prophylaxis, and some of these drugs for a very long period of time, and they may at this point have run out of funds. They’re well into this transplant course and are struggling. Not to mention the counseling support too from social work, because they again will tell you, “I don’t remember hearing about this. You know, I knew there was the first 200 days, but here we are, 2 years in and now I’m debilitated from these symptoms.” Plus, they have moved back home, and they don’t want to come as often. You know, sometimes management includes ECP [extracorporeal photopheresis], which requires a special center and requires frequent visits. They just did not have this on their radar, and they’ll tell you so. Also, I feel like they don’t want to come as often, so they want you to involve their local oncologists. A lot of local oncologists don’t feel comfortable, which is rightfully so. Therefore, the follow-up is much harder versus when they’re in your day hospital for the first 100 days and you’re already seeing them every day.

 I think that’s a really important point, which is that their psychosocial well-being and the quality of life becomes even more important in the chronic setting with chronic GVHD.

 So we talked a little bit about this. This is a chronic GVHD assessment. It has 10 points plus performance status. So the skin, the sweat glands, the fascia, the eyes, the mouth, the lungs, genital tract, weight loss. This is put together in the NIH [National Institutes of Health] clinical scoring and organ systems, which captures these organs on a scale of 0-3. So it’s a 4-point scale, at least you can see it goes from score 0 with no symptoms all the way to severe symptoms, and each of the organ sites that has 1 of these scores. This is put together in a global severity score. So mild chronic GVHD is 1-2 organs involved with no more than a score of 1, plus no lung involvement. Severe, on the other hand, is at least 1 organ with a score 3 or lung score of 2 or 3. And then, the moderate chronic is 3 or more organs with no more than a score of 1, or 1 organ, but not lung, with the score of 2, or lung with a score of 1. This gives us the opportunity to be uniform in our scoring of chronic GVHD. This is really critical, especially when we're starting to conduct large scale clinical trials, so that we can actually compare and use the same language across different centers.

 So what is the patient staging based on this criteria just discussed?

 We had a patient with dry eyes, then scleroderma changes, decrease in motion, and a drop in the FEV1, DLCO [diffusing capacity for carbon monoxide], and PFTs [pulmonary function tests]—that’s dyspnea. So this patient does get a lung score of at least 1 and obviously has a moderate graft-versus-host disease at this point. The lung score, as you can see from that scoring table, is the most prominent organ, which predicts very poor outcome at this point.

Shared insight on how to distinguish chronic GVHD from acute GVHD, as well as utilize appropriate methods to risk stratify disease. 

Corey S. Cutler, MD, MPH, FRCPC | Authors

Articles

Chronic GVHD: Prognoses and Future Directions in Care

Scenario 2: Treatment-Induced Damage in Chronic GVHD

Scenario 2: Selecting Therapy for Steroid-Refractory GVHD

Scenario 2: Belumosudil and Axatilimab as Treatment Options in cGVHD

Scenario 2: Ibrutinib and Ruxolitinib as Treatment Options in cGVHD

Scenario 2: Identifying Chronic GVHD and Risk Status