Michael Bishop, MD

I wanted to mention about the use of JAK inhibitors, especially in the AML [acute myeloid leukemia] setting, since we’ve been focusing on that as a pathway for relapse after transplant, the immune recognition issues. Many of the AMLs and MDS [myelodysplastic syndrome] lose class 2 expression after transplant and when the disease comes back. One of the issues for JAK inhibitors is that the regulation of class 2 is completely gamma-interferon mediated. It’s JAK1, JAK2 mediated. If you look at AML cells that have downregulated class 2, you can show specifically that you can re-express class 2 with gamma interferon, and that’s blocked completely by JAK/STAT inhibitors.

One of the risks of long-term chronic exposure to these JAK/STAT inhibitors, especially in AML and MDS after allotransplant, is the fact that you basically would prevent, in theory, not in reality, expression of class 2. And with the loss of class 2, then you have some way that the AML cells can evade immune detection by the donor T cells. It’s just a theoretical concern, and we and a few other groups…are trying to figure out how we can activate this pathway so that we can re-express class 2. But it’s clear that JAK/STAT inhibitors might be problematic in that setting.

Your group has beautifully shown some of that work. I would ask for your comments on it. One of the nice things, and again, we need long-term follow-up, is that REACH3 did not show an increase in leukemia progression. And the majority of patients on this trial had MDS and leukemia. That may be one mechanism, but it appears fortunately that we’re not seeing that clinically, or do you think that in the longer term in more patients we might see that?

That’s a very good point. What it does suggest to me is that if you have a patient who has relapsed after transplant, who has some GVHD [graft-vs-host disease] and has lost class 2 expression, then you want to stay away from a JAK inhibitor to control the graft-vs-host disease. But you’re right, in the REACH3 study, there was not any increase in relapse in that setting, or in the REACH2 study.

Right. That was a theoretical concern on both trials, and to see that compared to, especially in REACH3, where you got an investigator choice of treatment in steroid refractory, it was comforting. I don’t know, is that the right word I want to use, or I sleep a little bit better at night. But it comes back again that relapse is fortunately a rare commodity in patients with chronic graft-vs-host disease in general.

What I liked about the REACH3 study was especially that the patients had long-term stability, and the rates of progression were dramatically different in the 2 arms. Because again, aside from those rare patients who get photopheresis who are transformed clinically, the fact that you can prevent someone from getting worse chronic GVHD is a good thing. And they can live with that just fine.

You brought up an important point we haven’t talked about before and the other thing I like about ruxolitinib. If you are going to see a response, you generally see it on a relatively rapid basis, particularly in the acute graft-vs-host disease setting. There, where I can be thinking about alternative therapy, I’m going to have a pretty good idea. The chronic graft-vs-host disease is tougher, particularly some of the other changes, but still the effects are relatively rapid compared to ECP [extracorporeal photopheresis], where I’m going to give it that 8-week period before I’m going to call it.

It’s true, and the mechanism of action makes little sense, right, because what JAK inhibitors do, they block JAK/STAT signaling, and it turns out that a lot of this is mediated through gamma interferon, which binds to its receptor, and that’s JAK1, JAK2, and STAT1. That signaling pathway in the T cells is blocked, so the T cells cannot proliferate as quickly, and the T effector expansion is reduced. The percentage of those Th1 [T helper cell type 1]-positive cells goes way down, and it alters the expression of these proteins that allow T cells to traffic to sites of inflammation, which is what graft-vs-host disease is in the GI [gastrointestinal] tract. And in the GI tract and in the skin, the inflammatory effects of the conditioning and GVHD upregulate CXCL9, 10, and 11, which are the ligands that bind to CXCR3, which is the one receptor that’s upregulated through gamma interferon signaling.

What happens is that you get increased expression of those ligands and increased expression of the receptor on T cells, so the T cells get to these tissue sites of inflammation much faster, and they injure those tissue sites of inflammation. And what ruxolitinib does is it blocks both the T-cell side of the signaling, so the CXCR3 is not upregulated, but they also block the ligands in the tissues that bring the T cells into the tissue. Biologically it makes a lot of sense why this is a good anti-inflammatory and why it works in so many other illnesses, too.

What do you think? There are now 2 drugs approved by the FDA for the treatment of patients with chronic GVHD. It’s interesting that both were approved in single-arm, open-label studies. What do you think about the approval for the third drug, ruxolitinib?

Well, that will be coming. I don’t know if this is the best analogy but it’s like COVID-19. You have a terrible disease, we’re just happy to have something that potentially can work. Maybe we’re going to get to the luxury now of, that we can do well designing phase 3 studies and that we can start looking at some of the things you had mentioned before, as early intervention and not waiting for the steroid refractory. Let’s say well, can we use these at the first sign of chronic graft-vs-host disease and maybe they can be steroid sparing from the very beginning.

I’m excited. Like I said, I can remember the dark ages of graft-vs-host disease and when we didn’t understand. We truly don’t fully understand the biology, but just from the description of everything that you’ve said within the past hour, think about if you could see that pre-2000, none of that was understood. It just shows you how important doing basic science from an immunology standpoint is in studying these patients. I’m optimistic. Like I said, I wish I could start my training all over again because I think that the times would be better for patients.

Yes, it would be nice to do that. But it was such hard work training all those years. I’m glad I don’t have to do it again. It was a lot of fun talking to you, Mike.

I learned a lot and hopefully our audience did too.

I got the better end of this deal, but it is nice to hear. It’s reassuring knowing that we’re practicing similarly, and again, we’re optimistic for our patients.

Yes, absolutely. We hope that those who are listening got a little bit out of this as well. Thank you very much again, Mike.

Videos

Drs Michael Bishop and John DiPersio comment on clinical implications for the use of ruxolitinib in chronic GVHD and share insights on future directions for GVHD.

Role of Ruxolitinib in GVHD Treatment

Let me ask you also about, I don’t know if you’ve had the same length of experience, either in trials or after the ROCK inhibitor has been approved. When you have a patient on a JAK inhibitor, ruxolitinib, for chronic GVHD [graft-vs-host disease], and you get to a point where they’re not improving much more and they’re still complaining and not getting much better, you just told me that you tend to, unless they really decline, you probably keep them on if they’re stable. But what about adding a ROCK inhibitor, would you stop the JAK inhibitor, or would you add them both together?

Well, you know, that’s a good question. We have added on agents. I don’t have that large of an experience with ROCK inhibitors where I can say that. I’d be interested to hear what your experience is, but we have added on agents, as I mentioned before, with the hope that we’re still getting some benefit, but we need something extra. If we clearly see there’s zero response, we’re likely to stop the ruxolitinib. We have occasionally switched to ibrutinib. Whether that play makes any sense, you could argue. But again, as you know, when you’re getting to third- and fourth-line treatments for chronic graft-vs-host disease, you reach to whatever life preserver is there.

I would say, nobody’s had that much time with both drugs. We’ve obviously given JAK inhibitors, ruxolitinib, to many patients, and now we’re tending to add on a ROCK inhibitor to it and not discontinuing it because we have the same concerns that if you just stop it, there will be some patients who may flare. And they work through completely different mechanisms, and they work largely maybe even through different cells. ROCK inhibitors certainly have anti–T-cell function, but they also have inhibitory functions on monocytes and macrophages, and neutrophil enzyme and proteases, and things like that. We tend to add them together, and we’re going to see if the 2 together actually have benefit.

Just from a management standpoint, drug-drug interactions, what do your pharmacists say?

So far, they have said that there are no obvious drug-drug interactions, so we’ve not been dosing them differently. The ROCK inhibitors get dosed based on whether they’re on azoles or a proton pump inhibitor.

What about ibrutinib? Where do you put that in your armamentarium for chronic GVHD; are you skipping by it, are you using it? If people progress on JAK inhibitors, do they go to photopheresis or do they go on ibrutinib?

We so use a fair amount of ibrutinib. That would be next line for us. We do believe in, that’s probably a poor choice of words, but ECP [extracorporeal photopheresis] becomes our third line. But then we will think about the use of ibrutinib, and we do use a fair amount of ibrutinib in our chronic graft-vs-host disease, particularly if they have not had any significant response to ruxolitinib.

The only thing I caution about is that these patients have thrombocytopenia often with chronic graft-vs- host disease. A lot of my older patients already have cardiac problems. Some of the second-generation BTKs [Bruton tyrosine kinase inhibitors], some people are looking at acalabrutinib. I would be more comfortable if that had been well studied in chronic graft-vs-host disease because I feel more comfortable with it relative to potential adverse effects. I do think that’s part of the decision-making process of how I’m going to treat a patient, I am looking at those potential adverse effects and coming back again to quality of life. That was my hesitancy when you asked me about ibrutinib.

Yes. We’ve used, again like you, a fair amount of it, but I would say that it’s not nearly as commonly used as any of the other things we’ve been talking about.

They are our third- or fourth-line agent, depending upon the patient and their situation.

Exactly, and we’ll certainly go to clinical trials even before we put someone on ibrutinib, meaning that we aren’t as confident with the results, a small single-arm study. Although the results seem compelling, in the real world, our experience has not been as compelling. That’s been the hold up, and appropriately so. If the trials were done like the REACH3 study was done, I think we’d probably have more confidence and probably use it more frequently. It does have some unfortunate adverse effects from time to time in patients as well.

Expert hematologist/oncologists consider combination therapy with ROCK and JAK inhibitors for the treatment of chronic GVHD as well as the use of ibrutinib for disease management.

Practical Considerations for the Treatment of GVHD

There may be a certain degree of precision medicine that is escaping us here. Obviously, you and I have seen these, I’ve seen some patients with bad chronic GVHD [graft-vs-host disease] who have enormously impressive turnarounds with photopheresis, not many unfortunately. The question is for those patients in particular, what’s the biology of their disease? Why do they seem to respond so much better than the other 80% or 90% of patients who get photopheresis and at best, their disease sort of holds stable?

Do you think it is those patients whose T-regulatory cells [T-regs] do improve?

That’s about the only thing, nobody understands why, but we do see that in the responding patients that T-regs seem to improve.

Yes. We’ll see what happens with chronic GVHD, but the Holy Grail going forward is again, it’s when you get it and it’s bad, it’s bad…. The other thing, Mike, is that for all of these treatments, if you look at all of them as far as pulmonary responses, which is the most dreaded complication of chronic GVHD, progressive diminution of vital capacity and pulmonary function. If you look at all of them, Syndax [axatilimab], the ROCK inhibitor, Jakafi [ruxolitinib], photopheresis, the one area that doesn’t seem to improve even though you can improve the skin and muscle, and flexibility, and eyes and mouth, is the lungs. If you look at all these studies, the improvement in the lung disease has been negligible.

Yes. It’s always when they list the organs in terms of response, it’s always the last, and liver comes in a close second, but particularly in lungs because it’s so devastating clinically in what it does to patients’ quality of life. I agree with you, the biology there to understand why, as you were talking about before, it comes back to B- and T-cell biology, this endothelial damage and what we think is deposition of aberrant monoclonal antibodies. It is disappointing. And again, it comes back probably to your primary theme of treat early and treat aggressively before you see these significant changes occur because it can provide some stability. If I had stability in those patients with bronchiolitis obliterans, I would be happy on a relative scale.

Now, I wanted to ask you, what’s your policy and sort of your own institutional guidelines for when patients do have chronic GVHD and they’re on a JAK inhibitor, for instance, how long do you continue the treatment, indefinitely, or do you treat for 6 months, and then if there’s no further improvement, do you stop?

We would stop if there’s no improvement, but if we get close to complete response, we will try to taper. Personally, I don’t go from 10 to 5 mg, I’ll do instead of 10 mg BID [twice a day], I might go to 10 and 5 mg, and then 5 and 5 mg, rather than just jumping down. Whether that’s correct or not, I don’t know, but I’d rather do it like a steroid taper. I just don’t want that block off, and that might biologically, maybe it’s already inhibited enough. But I tend to try to taper, so if they’ve had an outstanding response, I try to taper off, but I make sure they’re off steroids first. We tend to keep ruxolitinib on for a long time as long as they’re tolerating it. In my experience, the cytopenias are quite manageable. I’ve had very few patients where I’ve had to stop because of adverse events.

Yes, I wanted to make that point. This was the reason why these things were never studied up front even though our laboratory had pushed this from the very beginning. No one wanted to do it because of this potential risk of cytopenias. In our mouse models, we showed that these drugs improved hematopoietic recovery, they didn’t decrease it. And then it probably has to do with the fact that they reduced GVHD.

Right, and the negative effects, exactly right, on the bone marrow.

The cytopenias we see when we put people on JAK inhibitors, we automatically attribute it to the drug, but we see them also in patients who aren’t being treated as a component of, especially acute GVHD.

Michael Bishop, MD, and John DiPersio, MD, PhD, discuss pulmonary complications associated with chronic GVHD and the management of cytopenias in patients treated with JAK inhibitors.

JAK Inhibitors: Managing Cytopenias in Chronic GVHD

 One of the things about a lot of clinical trials previously was that patients had to fail a half a mg [milligram] or a mg/kg [kilogram] of steroids for a month. The problem is that a lot of these patients that have chronic GvHD [graft-versus-host disease] is they’re weak, and they have a lot of muscle loss and you put them on that much steroids for a month, they just fall apart. There were a lot of trials we did not participate in because we couldn’t bring ourselves to torture people with that much steroids. A lot of them, get a lot of symptoms from high-dose steroids. They can’t sleep, they’re miserable, and that limited our participation in some of these chronic GvHD studies. It also begs for alternative therapies for chronic GvHD that are not steroids.

 You know, you hit on something very important is you’re right, you had to be defined as steroid refractory. I would give the NIH [National Institutes of Health] Consensus Conference some things where they go, you don’t have to be on a mg/kg. It could be that it’s just an extensive amount and you’re just not going anywhere. But I agree with you, we know that we need interventions that will allow us to be steroid sparing. We just know that these are going to be, the complications that will occur are unlimited. From steroid psychoses to myopathies, as you described, it’s very important to, I agree with you that having agents that we can add on and minimize toxicity in these patients is key.

 We have had a lot of exposure to many drugs over the years, too, in the context of small single-arm, open-label phase 2 studies in chronic GvHD which have led us in every direction but the right direction. I can tell you that there was a lot of interest and there were lots of believers and nonbelievers in things like Rituxan [rituximab], or regulatory T cells, and low dose IL-2 [interleukin-2], lots of things. I’m not saying that they don’t have merit, I’m just saying that none of these things were followed up with properly designed randomized trials to see if they benefit patients.

One of the problems is that we have a lot of difficulty, even though we have NIH consensus criteria for measuring chronic GvHD, whether it’s limited, extensive, or severe, and severe or not severe, it still is very complicated, multiorgan system staging which almost no one has time to do. And even if you have independent stagers at your center that do this on a regular basis, there’s enormous variability from visit to visit and from node to node. And it’s very hard to do this in a way that’s meaningful.

If you can’t measure the disease quantitatively in any way, then you can’t determine quantitatively if you’re making things better or not. And what you’re left with is your observation and the patient’s reported outcomes. One could argue that patient-reported outcomes are the most important. If someone has chronic GvHD and they have fascial involvement, or tendon involvement, or thickened skin and they can’t move and they can’t bend their joints, then you could give the patient a drug and if the patient clearly can move better and skin is clearly softer after 2 or 3 months of treatment, then you’d have some confidence that the drug is working. But, oftentimes, what happens is you walk into the room, and you know you’ve given the patient a new drug and you look at the patient and you ask the patient, “Well, how do you feel?” And the patient will say, “Well, I don’t know.” And then you look at the patient and you say, “Well, you look better,” and then the patient says, “Well, yeah, I might feel a little better.” And then you write down improved because it’s your bias. It’s also the patients responding to your cues. You want the drug to work, you walk in the room, and you say, “Ah, I think you’re a little bit better, what do you think?” “Ah, maybe I am a little bit better.”

There’s an enormous amount of physician and patient bias in measuring responses in chronic GvHD trials which, in my humble opinion, have limited the interpretation of the small trials that have been done, both with ibrutinib [Imbruvica] and with the ROCK [rho-kinase] inhibitor. I say that they both may be very effective and obviously they’re both approved now for the treatment of chronic GvHD. But, in a single-arm small open-label study where you have enormous observational biases, both from the patient and the physician, I have concerns about the real relative benefit of treatment.

 Before the NIH Consensus criteria, it was like, I know graft-versus-host disease when I see it and we had limited and chronic. This is trying to put some objective criteria because even in everything that we do, they’re subjective and I totally agree with you. We need better, and it’s because the disease is so complex, but at least we have some guidelines to do it. Just like the REACH3 study uses NIH criteria, and I think there is a difference. Before we had these, the comparisons, I mean you would go back to talk about the ECP [Extracorporeal Photopheresis] trials. I mean trying to interpret those is nearly impossible. We couldn’t even agree on how we grade skin. I know it’s imperfect, but at least it gives us some guidance and it’s evidenced by the number of large trials that we’re able to do now. I think that’s moved the field forward.

 And it’s funny you should say ECP because I would say, I don’t want to sound too heretic here, but I would say having treated lots of patients with all of these drugs that if there’s one approach that seems to work and actually reduce the extent of pure chronic GvHD in some patients, that’s clearly, in my humble opinion, that’s clinically obvious it’s ECP.

 It doesn’t help that many patients. But when patients have severe chronic GvHD and they get on ECP, some of these patients just dramatically improve.

 I mean, coming back to the REACH3 study where investigators had a choice of about 10 different treatments that they could use, including ibrutinib, which is I always find it interesting now that it only got a minority and that was a large European components, they may not have had access to it. But the number one choice was ECP, and there were patients who did respond, right? The number one choice for alternative was ECP, yet the ruxolitinib [Jakafi] arm was markedly superior in almost every aspect.

 Yes. And I also think that these medical therapies, the ROCK inhibitor, Jakafi as per the REACH3 study, and ibrutinib, the major take-home message and the newer Syndax trial with the CSF1 [colony stimulating factor 1] receptor antibody, this take-home message that I get from all of these studies is that the most important primary end point is time to progression or percentage of patients that progress. And that’s the thing that seems to be impressive in the REACH3 study, and that’s the best study that’s been done so far in chronic GvHD because it’s a randomized trial. Again, I go back to this issue of doing properly designed studies before you put all your money on your front runner here. Even though the ROCK inhibitor and ibrutinib were approved, I actually think that there’s much more solid evidence to support a JAK [janus kinase] inhibitor in this disease because of this well-designed randomized trial than anything else. Even though these other drugs may work just fine, and they could even work in the long-term better than Jakafi. I don’t know, but they haven’t stood the test of time.

 Yes. I don’t know if they have either. They’ll have to go through the randomized trials as well. With REACH3 is the durability of response and seeing the increase over time because again looking at this 24-week evaluation. But then, subsequently when you take it out to the 48 and beyond is seeing sustained and increasing degree of response. And that to me and the ability to get patients off steroids or a greater percentage of patients, at least having a dose reduction, those are my goals and for number one to be relatively well tolerated and convenient.

Drs Michael Bishop and John DiPersio comment on common challenges in measuring response in chronic GvHD and review clinical implication from the REACH3 trial.

Challenges in Managing Chronic GvHD

 The issues with chronic GvHD [graft-versus-host disease] are two things that I’m aware of that limit the incidence of chronic GvHD. Taking the T cells out, which causes lots of problems, we don’t do that. Although limited T-cell depletion and alpha-beta depletion and things like this have been used in children and adults with some success. And that’s reduced the rates of chronic GvHD and early intervention with posttransplant Cytoxan [cyclophosphamide] and antithymocyte globulin. Those are also effective. But how about the management of chronic GvHD, Mike? What’s your approach with patients who come in and have developed signs and symptoms and chronic GvHD?

 Multiple factors go into that. I always like to think, chronic graft-versus-host disease, it’s a far more muddied entity than those patients with clinical acute graft-versus-host disease. From several perspectives, what organs are involved? What is the severity of those organs? What are the complications that happen in regard in the posttransplant setting? All of a sudden, they had acute graft-versus-host disease and they develop a fungal infection, or they were on steroids and got avascular necrosis. Those issues will come into play of what agents I’m going to choose. Is the patient still on a calcineurin inhibitor? Then you and I would know that generally those patients, they’re beyond 3 months, and they’ve gone home, and they’re trying to resume some resemblance of a normal life again. And all of a sudden, we’re saying, well, now we need to start you on this new therapy.

And, just as you said, we need to nip it in the bud as quick as possible because this is going to likely be a problem that you’re going to have for several months to years. It can intend to include other organs eventually. And how do we come up with the strategy and tactics to try to have a person have a quality of life, keep them alive, and not have them have another complication and prevent a recurrence of another complication, be that fungal infection or, most importantly, and the reason they probably went to transplant, is to make sure their disease doesn’t come back. Although, if they’ve developed graft-versus-host disease, that’s the one good thing that we can think about. If they have chronic graft-versus-host disease, the probability of their leukemia and their lymphoma coming back drops down dramatically.

That’s how I get my global picture. And for localized skin, again eyes, mouth, and skin are the three most common we’ll see in chronic graft-versus-host disease, I will try to avoid systemic therapy if possible. As soon as I see a patient needs systemic therapy, when I see such as lung, kidney, or liver involvement, then I know I’m going to have to use systemic therapy. But I will try to limit it to maintain quality of life and to try to limit the toxicities of steroids. That’s my general approach.

 Yes. I agree. And one of the things is I’ve always been impressed of how little steroids do, too, for these patients with chronic GvHD.

Experts in hematology/oncology review factors to consider when approaching the management of chronic graft-versus-host disease.

Management of Chronic GvHD

In the acute GVHD [graft-vs-host disease] setting, after you have someone who’s been having ongoing diarrhea on a JAK inhibitor, and they’re not, this is acute. What are your third-line approaches to those patients?

 At our own institution [the University of Chicago], we like extracorporeal photopheresis. The reason I like that is because it’s not a direct drug intervention because there are already a number of agents. The agents we’d be looking to add would potentially be an anticytokine monoclonal antibody. We have looked potentially at another kinase inhibitor, like in ibrutinib. We always try to get on a clinical trial of course, right?

Usually, the clinical trials are available if they have to be. They’ve had only frontline therapy with steroids. But we tend to use a lot of ruxolitinib in that setting.

I like extracorporeal photopheresis because of lack of drug interaction. We can have responsiveness, and we’ll continue the ruxolitinib through that with the idea hopefully that we’re going to get steroid sparing and get the disease under control. Whether that’s correct biologically, I don’t know. But the only problem with extracorporeal photopheresis is that I get a lot of pushback from patients having to come in twice a week for those first 4 to 8 weeks trying to get it in. You know that’s the last thing they want to do. As a matter of fact, they’ll scream and bite before they do it. But that’s generally our approach.

 Yes, it’s a major commitment on the part of patients. I don’t know if everyone understands how expensive photopheresis is. Most of us have not seen any hospital bills, but the cost of a year of photopheresis twice a week every other week is around $350,000 to $400,000. That’s quite substantial when you think about Medicare paying transplant centers only around $70,000 for an allogeneic stem cell transplant.

This can be very expensive, and it’s also tough on the patients, right? They get wiped out and they must travel sometimes long distances to get their collections. When they’re outpatients, they need to stay overnight and get it 2 days in a row and then come back in a couple of weeks. How we do photopheresis in the defined best of care with this approach has not been worked out very well.

And also, how it works. We don’t even know how it works. There are lots of theories, so we’re giving a treatment that’s phenomenally difficult and expensive, and we’re not really sure how it works. It’s frustrating for us as physicians to be in the middle of a treatment that’s complicated and expensive, and when we don’t know the mechanism by which it might affect patients.

I also wanted to echo your comments about clinical trials. For anybody who has steroid-refractory graft-vs- host disease, there’s a drug that’s approved, Jakafi. It’s perfectly appropriately to treat any patient who has steroid-refractory GVHD with that FDA-approved drug, and it’s effective as based on the phase 2 studies and the randomized phase 3, REACH2 study.

The other drugs out there that we might use, including photopheresis, would be primarily for those severely progressing patients in the hospital. We might consider, in addition its clinical trials, we have used quite a bit of vedolizumab as an inhibitor of alpha-4 beta-7, which is the integrin that’s key for trafficking of T cells to the GI [gastrointestinal] tract. It’s approved for the treatment of patients with IBD [inflammatory bowel disease]. And it may help some patients with that particularly aggressive GI graft-vs-host disease.

What we found and what others have found is that sometimes, if you treat that with vedolizumab, people get worsening skin graft-vs-host disease ironically, which is interesting. So far, the randomized trials of vedolizumab have not shown a particular differential benefit of this drug over standard of care. As far as what’s out there, there are some interesting trials looking at antibodies to specific T-cell markers.

There’s a ricin conjugated CD3/CD7 combination that was effective but caused a lot of problems. It was put on hold, and it’s about ready to be restarted through the CTN [Clinical Trials Network]. It’s called T-Guard, which has been used in these very severe cases. We get back to the issue of whether it’s better to try to wait for people to get this severe GVHD or try to intervene early with some more targeted therapies, so you don’t let the disease get so progressive.

John DiPersio, MD, PhD, and Michael Bishop, MD, discuss third-line treatment options for patients with acute and steroid-refractory GVHD.

Michael Bishop, MD | Authors

Articles

Role of Ruxolitinib in GVHD Treatment

Practical Considerations for the Treatment of GVHD

JAK Inhibitors: Managing Cytopenias in Chronic GVHD

Challenges in Managing Chronic GvHD

Management of Chronic GvHD

Third-Line Treatment Approaches for Acute GVHD