Transplant-Associated GvHD - Episode 4

Case 1: The Role of Ruxolitinib in Steroid-Refractory Acute GVHD

Targeted Oncology

The panelists discuss the role of ruxolitinib steroid-refractory acute GVHD and comment on unmet needs in treating this patient population, including fecal transplants.

Yi-Bin Chen, MD: Would you say that based on the findings of this trial, but also the REACH1 trial and your experience itself, that ruxolitinib has become the standard of care for steroid-refractory acute GVHD [graft vs host disease] for your patients?

Pashna N. Munshi, MD: Being approved for this indication and having promising results in a large study like this, it’s hard to deny your patients this drug when you want to get them off steroids. I have been reaching out to use ruxolitinib, and initially, depending on what their blood counts are, I feel comfortable starting even at a low dose of 5 mg twice a day and escalating that if need be depending on how they tolerate it.

Yi-Bin Chen, MD: Dr Chao, in North Carolina, has ruxolitinib become fairly standard treatment for steroid-refractory acute graft vs host disease?

Nelson Chao, MD: It has. As long as there’s not a competing clinical trial, we have and used ruxolitinib. Even before this trial and before the final results.

Yi-Bin Chen, MD: How has your anecdotal overall experience been in this setting?

Nelson Chao, MD: It’s been close. It’s not the easiest drug to use in these patients because, 25 after an anecdotal transplant, the counts are pretty fragile. You have to be careful with the play counts but sometimes with their neutrophil count as well.

Pashna N. Munshi, MD: To add to that, when we’re also treating leukemia patients, thinking about how we prevent relapse and if you want to start them on ruxolitinib dose, all that also impacts your ability to treat them effectively if they have cytopenia in addition to this.

Yi-Bin Chen, MD: All of us would agree that while the REACH2 results are impressive, and we applaud the investigators for conducting a phase 3 randomized trial in that setting—which is quite rare—there’s still room for improvement. What we showed was that while there’s a compelling overall response rate, the durable response rate at 8 weeks out remains in the minority of patients. Dr Chao, what do you think the unmet needs are going forward for steroid-refractory acute GVHD? Do we need better drugs, better trials, better ways to prevent, or all of those things? What do you think we most need to focus on?

Nelson Chao, MD: We need better drugs. I agree with you. If you look at the durability, it’s better than some things we’ve had, but the overall response and the length of response are probably not as good as we would like. The trial design people have complained about the special alternative therapy with 10 choices. That’s reality, but limiting to some of the other choices would have made it cleaner. It’s always true that your results can look better because your drug is better or because the controls are worse. Sometimes it’s hard to tell. There are still a lot of unmet needs.

Yi-Bin Chen, MD: Dr Munshi, what are your thoughts on that?

Pashna N. Munshi, MD: I agree because we still have nonresponders, even to this combination. What happens to those patients? How do we get them off steroids? To Dr Chao’s initial comment, do we need steroids at all? Can we use something else steroid sparing as frontline therapy? We don’t have answers to that.

Yi-Bin Chen, MD: The next few years will hopefully be exciting in graft vs host disease research in general. There’s been more interest, and we have more clinical trials. We’ve all seen that and participated. We’re all hopeful that we can make some more progress even beyond this to ultimately improve the outcomes for our patients.

Yi-Bin Chen, MD: Dr Munshi, there are several agents under investigation. Are there any that you or your center are most excited about?

Pashna N. Munshi, MD: I’d be happy to hear your thoughts on the alpha-1 antitrypsin drug that was used in the first line after steroid-refractory acute GVHD. Bortezomib is a friendly fire around here. It’s easily available, and there was a phase 2 randomized trial that looked at bortezomib with TAC [docetaxel, doxorubicin hydrochloride, cyclophosphamide] methotrexate and then with TAC sirolimus. They’re not robust data. It looked like the combination with sirolimus had about a 15% incidence of grade 2 to 4 acute GVHD compared with the standard TAC methotrexate, which happens to be 30% to 40% incidents of acute GVHD. Maybe in some cases, you could use bortezomib. But when you look at the data closely, there weren’t impressive responses in grade 3 or 4 acute GVHD. It’s something that’s readily available. You can see in the data that was the other JAK1 inhibitor didn’t pan out when used with TAC [docetaxel, doxorubicin hydrochloride, cyclophosphamide] methotrexate for profile access. It didn’t show a lot of difference. I haven’t been using any other monoclonal antibodies or things like that, but I’d be interested to know what you and Dr Chao do in your practices.

Yi-Bin Chen, MD: There were impressive data from using alpha-1 antitrypsin necessarily refractory setting from both Michigan and Seattle, and it’s being tested in the up-front setting for clinical high-risk graft vs host disease in a trial run by the CTN [Clinical Trials Network]. Here in Boston, in addition to ruxolitinib, when patients have steroid-refractory lower GI acute graft vs host disease, we’ve been pursuing 2 other modalities of therapy. One is the monoclonal antibody, vedolizumab, which is approved for inflammatory bowel disease and targets a mediator of lymphocyte trafficking to the intestine. I’ve conducted clinical trials using that agent, and we’ve seen some responses to it, but it also does not appear to be a home run. Earlier use is better than using it in the very steroid-refractory setting.

The other avenue we’ve looked at is the role of the microbiome in transplantation, meaning the diversity of the bacterial colony in one’s intestines. A lot of associative studies done by Dr Chao’s colleagues, also done by investigators at [Memorial] Sloan Kettering [Cancer Center] and other sites, have shown that patients with dysbiosis or restricted microbiome diversity predict a higher incidence of graft vs host disease. That’s led some of us to pursue the role of trying to restore diversity as a treatment for acute graft vs host disease. We’ve done third-party fecal microbiota transplants right after transplant empirically to prevent graft vs host disease. We’ll have an upcoming trial to treat steroid-refractory acute GVHD. There have been anecdotal series around the world that have used fecal microbiota transplantation with some success to treat graft vs host diseases as well. It’s something that bears watching. It is an interesting world that requires us to think about what is a drug and how to manufacture it and then to be sure of the contents of something as we’re doing it. Dr Chao, because your center has done some work on the microbiome, what are your thoughts on the future of that?

Nelson Chao, MD: That’s promising. The correlation is clear. We need to prove causality, and then if that’s the case, fecal transplants work quite well for Clostridium difficile. It works well for difficult-to-treat diseases like that.

Yi-Bin Chen, MD: That wraps up case 1.

This transcript has been edited for clarity.