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.
John DiPersio, MD, PhD: 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.
Michael Bishop, MD: 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?
John DiPersio, MD, PhD: 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.
Michael Bishop, MD: 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.
John DiPersio, MD, PhD: 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.
Michael Bishop, MD: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.
John DiPersio, MD, PhD: 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.
Michael Bishop, MD: Right.
John DiPersio, MD, PhD: 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?
Michael Bishop, MD: 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.
John DiPersio, MD, PhD: 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.
Michael Bishop, MD: Same here.
John DiPersio, MD, PhD: I learned a lot and hopefully our audience did too.
Michael Bishop, MD: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.
John DiPersio, MD, PhD: Yes, absolutely. We hope that those who are listening got a little bit out of this as well. Thank you very much again, Mike.
Michael Bishop, MD: Thank you.
Transcript Edited for Clarity