The Ongoing Fight Against Acute GvHD - Episode 7
John F. DiPersio, MD, PhD: First, you have to establish safety in the prophylaxis setting. You have to have enough patients to be convinced that it works, and not only that it works but that it is sufficiently tolerable, because 1 of the things is that you don’t want this to affect engraftment. In the preclinical models, we showed, and others showed as well, that actually, the opposite occurs in a mouse model, that engraftment is enhanced by JAK inhibition. In spite of that, it was hard to get anyone to consider early intervention with JAK inhibitors, because people were worried that if something happened, like graft failure, that would end the drug’s journey forward to FDA approval.
But I still think that if you look at the mouse models, the preclinical models, there’s absolutely no doubt that late intervention has, at best, a modest effect. It can treat acute GVHD [graft-vs-host disease] in a mouse model, and it can reverse it to a limited degree. But the mice often will go on and die if the disease is already severe and established. It’s what we see in humans. It does a nice job. But patients still suffer along the way, and they don’t snap around completely in a few days. So I think early intervention is the way to go.
Also, chronic GVHD is another disease that is terrible. It can happen almost at any time, but usually late after transplant. The interventions so far have been, at best, palliative. One drug is approved, and there are a few other drugs that are out there. But once chronic GVHD is established, it is hard to reverse it. It’s only probably possible to limit its progression. And there’s some debate about this. I don’t want to say that the currently approved drug for chronic GVHD is ineffective. I would just say that it’s got limited efficacy at really improving patients’ quality of life. Biologically, early intervention is the way to go there too, because of how GVHD occurs and how B cells are engaged in the chronic GVHD process. It makes some sense that these early interventions would be the way to actually prevent, ironically, late complications of transplant, such as chronic GVHD.
It will be very interesting to see what the randomized trial shows for chronic GVHD. I haven’t seen anything or heard anything, and I don’t know if it will be statistically significant, but my prediction is that there will be less chronic GVHD in the treated group than in the standard-of-care group and that if these things are used early on in a prophylactic setting, there would be a much bigger difference in chronic GVHD. Also, it will have a much bigger impact on acute GVHD. That’s No. 1. So you have to establish safety. The safety is engraftment, blood count recovery, and viral infections, because viruses are eliminated through gamma interferon signaling. That pathway is going to be blocked with JAK inhibition. That’s something that people have to look at rates of viral infection, not only CMV [cytomegalovirus], but HSV [herpes simplex virus] and adeno and EBV [Epstein-Barr virus] as well. Those things will have to be looked at carefully in the long term while you’re on this drug.
We’ve been looking at that for a long time in our chronic GVHD patients on the extended-access protocol for Jakafi and looking at DNA copy number for EBV and CMV to see if there are any differences there. That has to be looked at. Finally, relapse, because relapse still—along with GVHD—equally contributes to death after transplant. So you don’t want to eliminate GVHD but then have a higher rate of relapse. The best study to really look at this would be transplantation in patients who are less than 60 years old and in remission at the time of transplant. The number of patients in remission have to be balanced for MRD [minimal residual disease] positive and negative in both groups. One group gets prophylactic Jakafi, and the other does not. Then you look at engraftment, and you look at engraftment of neutrophils and platelets, and you look at chimerism, and you look at viral infections, and you look at relapse, and you look at GVHD, and you look at chronic GvHD. That’s a big, expensive, and complicated long-term trial. The question is, will anyone have the stomach to design and execute a study like that?
The second future for GVHD is there are a number of other things that are being developed. We could spend hours talking about them. Because we’ve been focused on the JAK pathway, suffice it to say there are many other approaches that may have merit, for the treatment of established acute GVHD but also for prophylaxis. Those have to be explored. I mean, they run the gamut of costimulatory blockade to antibodies directed to specific T-cell subsets, cellular therapies, small-molecule inhibitors, on and on. I could spend days talking about them. That’s the second thing.
The third thing is, JAK inhibitors are they’re chemical structures, and those chemical structures can be modified and optimized. And you could potentially design that second- and third-generation Jakafi, which has properties that, because of the structure of the molecules, may inhibit JAK signaling pathways but not result in some of the toxicities with JAK inhibitors like thrombocytopenia and anemia. It’s hard to understand how that could happen since those 2 kinases are very important in hematopoietic growth factor signaling. But there are potentially, in the future, additional JAK inhibitors that could be designed—either of them might be better tolerated or have less hematopoietic toxicity and the same amount of anti-GVHD effects.
And then finally, JAK inhibitors have a limited half-life. You take them twice a day, but if you have raging production of gamma interferon and IL-6 signaling, it is conceivable that if you cannot suppress those signaling pathways 100% all day every day, you’re going to fail in your ability to block GVHD. The other structural changes to some of these molecules could be that they could be designed to have a longer half-life. There are many ways to do that. But the half-life issue is so that they consistently, over a long period of time, for every minute of the day, block those 2 pathways very effectively. Those are some of the things that we can look forward to in the future.
Transcript edited for clarity.