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ASH 2021 | Developments within the GvHD treatment landscape

John DiPersio, MD, PhD, Washington University School of Medicine, Saint Louis, MO, describes recent advancements in the field of chronic graft-versus-host disease (cGvHD) treatment. He highlights the development of belimumab, ROCK inhibitors such as belumosudil, as well as Janus kinase (JAK) inhibitors, which have demonstrated efficacy in double-blind randomized trials. Novel CSF-1 inhibitors are additionally mentioned, which block the activity of pro-inflammatory macrophages in cGvHD. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

Obviously there are several important advances in the treatment of chronic GvHD. Number one, there’s been a recent approval of a drug called Rezurock, which is a ROCK inhibitor, which seems to have a positive impact on all sorts of different kinds of chronic GvHD, even lung-associated chronic GvHD, which is surprising. So that drug was recently approved and now more studies are being done with that drug...

Obviously there are several important advances in the treatment of chronic GvHD. Number one, there’s been a recent approval of a drug called Rezurock, which is a ROCK inhibitor, which seems to have a positive impact on all sorts of different kinds of chronic GvHD, even lung-associated chronic GvHD, which is surprising. So that drug was recently approved and now more studies are being done with that drug. Belimumab, which I just mentioned is another drug that’s we’re targeting the B cell arm of the GvHD effort, which includes both T cells and B cells. And the other treatments have to do with the use of JAK inhibitors. And again, JAK inhibitors, when given early they can block both acute and chronic GvHD. But after the fact, after one develops chronic GvHD, randomized studies have just shown that as we previously showed with acute GvHD, that JAK inhibitors will actually provide a benefit to patients in a randomized study.

So JAK inhibitor, interestingly enough is the only trial done in a randomized fashion in the chronic GvHD setting. So the effects were significant. I wouldn’t say they were mind blowing or anything, but they were significant and it got approval for the drug. And the most important part of it is that it was done through a randomized study, which is really important for assessing the impact of chronic GvHD by various pharmacologic interventions, because there’s a lot of investigator, physician and patient bias. When you go on a trial and you have a chronic condition like chronic GvHD, and you give the patient a drug and you walk in the room and you say, “Are you better? You look better.” And the patient goes, “Well, I guess I feel a little better.” And so you write down improved.

So that’s not really the best way to do it. The best way to do it is to blind the physician and the healthcare givers and the patient to the drugs they’re getting and do a truly randomized blinded study. And that’s what the ruxolitinib study did. And no other studies have done. So ibrutinib is approved, Rezurock which is the ROCK inhibitor was approved, but they were approved with single arm studies. So there’s a third novel in addition belimumab, which was a small pilot single arm study. There’s another drug called a CSF-1 receptor antagonist, and that’s made by Syndax. And that blocks the CSF1 receptor which is on macrophages. And it turns out that macrophages are involved with this chronic inflammatory response. And the key to understanding use of this antibody, which blocks signaling through the macrophages is that macrophages that are blocked early on after transplant actually cause more graft versus host disease because the macrophages that are present in the host are suppressive.

And when you kill them with this antibody, there’s more GvHD. But when given later, the macrophages are pro-inflammatory. And so the thought is that by blocking this receptor, you inhibit the function of macrophages late when people are already engrafted and aren’t at risk for increased acute GvHD. And what happens is they have less in the way of macrophage activation, which is a huge component of chronic GvHD. And so the theory is that this will be effective as well and time will tell. They’ve done some preliminary studies that was reported last year. More are being reported at this meeting this year. And again, the definitive way to prove any drug is effective in chronic GvHD is to do a randomized, double blind perspective trial. And so that needs to be done. It may never be done, but it should be done.

 

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