Yi-Bin Chen, MD, reviews the currently available FDA-approved therapies for the management of steroid-refractory chronic GvHD.
Matt Fowler: Let’s transition over to treatment options for steroid-refractory disease. Could you review the FDA-approved therapies for steroid-refractory chronic GVHD [graft-vs-host disease], and then specifically, the mechanisms of action for ibrutinib, ruxolitinib, and belumosudil?
Yi-Bin Chen, MD: Excitingly, we’ve had 3 recent approvals in the clinical setting of steroid-refractory chronic graft-vs-host disease. All credit goes to the investigators, and I’m thankful for the investment by the companies that have developed these agents and take an interest in our patients to conduct well-designed clinical trials and to gain regulatory approval. It certainly has created a lot of interest in our field and given our patients more options that hopefully will improve their outcomes.
The first agent that was approved was the oral Bruton tyrosine kinase inhibitor ibrutinib. This was in 2017. Ibrutinib is more well known for its approvals to treat various B-cell non-Hodgkin lymphomas. What investigators realized over the last decade and a half is that, while acute graft-vs-host disease is much more of a clear-cut T-cell Th1 immunological response, chronic graft-vs-host disease involves a lot of pathways that may be active in certain patients. This includes regulatory T cells and your B cells. A lot of the B-cell activity was shown in the sense of sex-mismatched transplants where anti-Y chromosome antibodies were present with a female donor and a male recipient combination. That signature was correlated with much worse chronic graft-vs-host disease. That led to a lot of B-cell therapies being developed, including the CD20 antibodies, such as rituximab, and then ibrutinib as well. Ibrutinib was surprisingly approved on the strength of a single-center clinical trial that involved only 42 patients as published by Dave Miklos and colleagues. Ibrutinib, in that single-center paper, had a response rate of about 60% to 70%. It showed some durable responses, and it showed some complete responses.
Complete response is an end point that we rarely achieve in patients with chronic graft-vs-host disease, so it’s difficult to ignore those results. There was no controlled population, so all patients and providers knew what arm patients were on. Given that this disease is a bit subjective and heterogeneous in how we judge response, one has to be somewhat skeptical. That’s not to knock the trial, but it’s a small trial without a control arm. Nevertheless, it was approved and became an option for our patients. In the real world, ibrutinib has proven to be a bit less efficacious than that study would suggest and a bit more difficult to use. It has well-known cardiac toxicities, diarrhea, and muscle cramps, and it has the most immunosuppressive action of any of the newer agents that are approved. We tend to not use ibrutinib very much at all in our current clinical practice for chronic graft-vs-host disease. The series of real-world experiences would somewhat support that less than enthusiastic anecdotal experience with the agent.
Of the 2 agents approved in the last years, the first was belumosudil. This oral agent is a ROCK2 inhibitor. ROCK2 is thought to be very active in the cascade of fibrosis, so putting down scar tissue in addition to ROCK2 is thought to not only inhibit fibrosis but also shift the T-cell balance to more supporting regulatory T cells. That was the rationale for using this in chronic graft-vs-host disease. Fibrosis is the pathological hallmark, so if we biopsy any tissue in a patient with chronic graft-vs-host disease, fibrosis is what you see. It’s thought that by inhibition of the ROCK2 kinase, we could halt fibrosis and even reverse it. This was 1 of the newer waves of therapies in which we moved away from pathways of immunosuppression to target more pathways of inflammation or fibrosis in this disease, to be more effective but also less harmful. We got access to this in the early fall, and we’ve written a handful of prescriptions for patients. It’s well tolerated from a safety perspective. We knew that from the pivotal ROCKstar trial, but we haven’t had a lot of experience to be able to definitively say how effective it is in a real-world setting. The findings in ROCKstar were impressive. There were over 70% overall response rates, but that was a trial where all patients were treated with the agent, so it’s tough to know what that would look like in a blinded control trial. It would be interesting to see what the real-world experience is.
The third agent approved was ruxolitinib. Ruxolitinib was well known to us from our experience in myeloproliferative disease and its recent approval in steroid-refractory acute graft-vs-host disease. Many of us have been using ruxolitinib for the last few years in steroid-refractory chronic graft-vs-host disease because of the anecdotes and our experience that it was efficacious. Ruxolitinib works by blocking JAK1 and JAK2, and this hits several pathways of inflammation. It probably has actions in lymphocyte trafficking. It has actions to support regulatory T cells. All in all, it’s a powerful anti-inflammatory agent that’s well tolerated. Right now, it’s the standard in terms of second-line therapy for chronic graft-vs-host disease.
Matt Fowler: Perfect.
Transcript Edited for Clarity