Treating Acute GVHD With Novel Strategies

Insights From: Joseph Antin, MD, Dana-Farber Cancer Institute; Corey S. Cutler, MD, MPH, FRCPC, Dana-Farber Cancer Institute



Transcript: 

Corey S. Cutler, MD, MPH, FRCPC: There are evolving data with ruxolitinib in GVHD [graft-vs-host disease]. The initial publications were retrospective in nature and really were very promissory with very, very high response rates for individuals who received these drugs in the second- or third-line setting. We then went on to do formal prospective studies. And the most important 1 to date is the REACH1 study that was recently published and led to the approval of ruxolitinib for steroid-refractory acute GVHD. It’s important to recognize that response rate in that trial was approximately 55%. It was for a group of patients who were relatively selected because they met the entry criteria to a clinical trial. In fact, the FDA label is based only on the patients who received ruxolitinib for primary refractory acute graft-vs-host disease.

Probably more important is the REACH2 study, which is a randomized trial. It has completed accrual, but we do not know the data yet. That was a large trial that evaluated ruxolitinib for steroid-refractory acute GVHD against best-available care or the physician’s choice. Physicians do have a choice of a number of other agents that we can reach for in the setting of acute graft-vs-host disease. Maybe you could just tell us a few agents that we have traditionally used in that setting and how you feel they work in comparison with ruxolitinib.

Joseph Antin, MD: We’ve done a lot of those studies. Unfortunately, many of them have good response rates but poor survival. Antithymocyte globulin is an example of that. For steroid-resistant GVHD, there’s probably a 60% response rate with antithymocyte globulin, and a 20%, 25% survival rate.

Dr Cutler and I, and our colleague Stephanie Lee, did a randomized trial of daclizumab, which is an anti-IL2 receptor antibody, a number of years ago. Same story. That is, we were all convinced that daclizumab worked great. There was an anti-IL2 receptor antibody. It should really only target activated T cells. We had been using it in a very optimistic fashion in phase II studies, and then when we did a randomized trial we found not only did it not work but it actually increased mortality and was less effective than steroid plus placebo.

Through the BMTCTN, the Blood and Marrow Transplant Clinical Trials Network, we evaluated 4 drugs to supplement steroids, all of which had been shown in some sort of phase II trial to have efficacy. These included pentostatin, Ontak, Enbrel, and mycophenolate mofetil. We initially did a pick-the-winner study where all the drugs were compared in a 4-arm phase II trial, and it turned out that they were relatively similar in efficacy, although the mycophenolate seemed to be a little more efficacious and a little less toxic. We then conducted a phase III trial, a randomized double-blind phase III trial, of the combination of mycophenolate mofetil and CellCept plus prednisone versus prednisone plus placebo. Shockingly, there was 0 benefit to the addition of mycophenolate.

There is no conventional therapy that we know is beneficial in this context. I should point out that although the REACH trials so far have been interesting in steroid-resistant GVHD, nobody wants to treat steroid-resistant GVHD. Where you want to treat is up front. You want to use a more effective treatment up front to prevent them from becoming steroid resistant, and those are the trials that I think will ultimately move the field forward.

Corey S. Cutler, MD, MPH, FRCPC: One of those trials is being conducted now, actually several of them are being conducted. Along the JAK inhibitor line is the trial that’s being conducted with itacitinib, and so that is the GRAVITAS-301 study that also has completed accrual. As you mentioned, that is a trial for steroid-naïve patients who have grade 2 to 4 graft-vs-host disease and who are going to be started on corticosteroids. Those individuals are being randomized to steroids alone, or steroids plus itacitinib. And exactly as you say, the goal here is to increase response rates early on, to reduce the toxicities, and the morbidities from corticosteroids, and to prevent more individuals from becoming steroid resistant.

As a clinical trialist it’s great to see that we are actually as a community doing these randomized, blinded, well-designed, well-controlled studies. There are studies like these that will eventually be practice changing, we hope. If they’re not practice changing because they’re negative, then we’ve learned important things, and we move on to use other things, such as more effective approaches to the prevention of acute GVHD, which is in fact 1 step before more effectively treating acute GVHD. But preventing a larger number of cases is probably the next best step.

Joseph Antin, MD: Another interesting drug that addresses the regulatory T-cell issue to significance is alpha-1-antitrypsin. This is a drug that also seems to have excellent activity in phase II settings. It hasn’t started, but it will be conducted by the Blood and Marrow Transplant Clinical Trials Network in another randomized trial. This, of course, is not intrinsically immunosuppressive, but it has anti-inflammatory components. It does increase regulatory T cells. Yet another example, along with itacitinib and others, of ways we may be able to modulate graft-vs-host disease without paralyzing the immune response.

Transcript Edited for Clarity
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