Future of Chronic GvHD

Video

A look into the future of chronic GvHD and which treatment options patients the panel is most excited about.

Transcript:

Corey Cutler, MD, MPH, FRCPC: What about the up-and-coming next compound in [graft-vs-host disease]? Very recently, axatilimab results were published in the Journal of Clinical Oncology. Carrie Kitko was the lead author. Does anyone want to discuss where this compound is going and what we hope to see from it in the future?

Doris M. Ponce, MD: I can comment on that. CSF1 inhibitor is a novel agent, and it’s added to the armamentarium for our patients. It was very interesting as the patient population participated in the clinical trial. What we’re learning so far is that patients were heavily pretreated. They had very advanced chronic graft-vs-host disease [GVHD]. The initial trial shows that it was safe and that patients were able to achieve a clinical response. In the inter-analysis that we’re hoping for, the trial accrues ahead of time, which speaks to the unmet need that we have in chronic graft-vs-host disease. If our patient failed all the available FDA-approved drugs, you’re left asking, “What are my options?” A clinical trial that provides that unmet need is something that we need. If axatilimab gets FDA approval, maybe that will be part of the armamentarium that we have.

Corey Cutler, MD, MPH, FRCPC: I agree. What exciting new things did you see at ASH [American Society of Hematology Annual Meeting]? Anything interesting? Hannah, why don’t you start?

Hannah K. Choe, MD: They reported on the glasdegib results for the hedgehog signaling. They saw some benefit there, and that was targeting sclerodermatous chronic GVHD, which is 1 of the 2 greatest challenges of chronic GVHD; [the other is] lung. It was exciting to see that there’s some promising movement there.

Yi-Bin Chen, MD: It’s an interesting compound. It’s hedgehog inhibitor. There is early preclinical work suggesting that the cascade is much involved in fibrosis. That goes to a shift in chronic GVHD therapy, from immunosuppression toward targeting fibrosis, just as axatilimab is designed to do. We did early work with another hedgehog inhibitor, or smoothened inhibitor, called sonidegib, which is FDA approved for the treatment of locally invasive basal cell carcinoma. We did a phase 1 trial years ago, and it looks exactly like their experience here. We saw some responses in scleroderma, but therapy was limited by the toxicity of the drug. The abstract reported here claimed myalgias and muscle cramps as the big thing. Our experience was a lot of excessive toxicity that we couldn’t explain. We didn’t think it was attributed to the drug itself because that’s not what the experience was in basal cell [carcinoma], but we couldn’t explain it otherwise. Overall, looking at fibrosis—the pathological hallmark of severe chronic GVHD—is an absolute must if we think we have any chance of reversing this.

Corey Cutler, MD, MPH, FRCPC: Has anyone used the specific fibrosis inhibitors, like pirfenidone or nintedanib, in chronic GVHD?

Yi-Bin Chen, MD: I haven’t prescribed it. When I worked with my pulmonary colleagues in severe cases of BOS [bronchiolitis obliterans syndrome], their chest CT is a bit atypical in appearance. It can look like idiopathic pulmonary fibrosis, which is what these agents are approved for. They’ve been prescribed at times, and it’s anecdotal. I’ve talked to colleagues who’ve used it anecdotally. I don’t think there’s a huge success rate, and it highlights those 2 manifestations we talked about—severe sclerodermatous disease and end-stage BOS—as chronic GVHD that really needs [this treatment].

Corey Cutler, MD, MPH, FRCPC: We’re particularly excited about the role of belumosudil in BOS. We’ll be enrolling patients to study belumosudil in that disease. What about regulatory T cells? They’re extremely important. We think of them as the breaks of the immune system. What else is out there?

Yi-Bin Chen, MD: Donor-derived regulatory T cells have been thrown about for years, and there have been pockets of people using them for prophylaxis and treatment. You guys have an experience doing the early trial, right?

Corey Cutler, MD, MPH, FRCPC: There 2 lines of evidence from our institution [Dana-Farber Cancer Institute]. First, John Koreth has led a number of studies using IL-2 at T-regulatory-enhancing doses. The trials are difficult because the compound is an injectable and can’t be prepared in big batches, but the trials were very positive and had very interesting biologic correlates. In the patients who responded, regulatory T cells went up, suggesting that we know the mechanism of action. We’re embarking on a trial with Leslie Kean on ex-vivo expanded regulatory T cells.

Yi-Bin Chen, MD: Is this from the donor, or is it a third party?

Corey Cutler, MD, MPH, FRCPC: These are a donor derived. That trial is getting underway shortly. Anything else? What else did you see at ASH that was particularly interesting in the chronic space?

Hannah K. Choe, MD: We had donor-derived T-regulatory cell results that they shared as well, and that showed the dose.

Hannah K. Choe, MD: Having the higher dose obviously has a better benefit. I was surprised by the duration of the T-regulatory cells still being identified and persistent beyond a year. That’s big. As we talked about before, with the combination we’re using with JAK inhibition and ROCK inhibition in practice but maybe not by the label, there were data shown with a combined JAK1/2–ROCK1/2 inhibitor. Those data need a little more exploration, but they’re obviously very promising in only 22 patients so far. I’d like to see the off-target effects and the tolerability of that drug in a larger study.

Doris M. Ponce, MD: I want to add 1 more thing. There was a study for up-front chronic graft-vs-host disease using itacitinib. That was an interesting study design. They have 2 doses of itacitinib with a control arm, which was corticosteroids. The higher dose of itacitinib was associated with a better overall response at 6 months compared with control. What’s interesting is that out of the responders, around 50%, 32% had achieved CR [complete response], which we rarely see in chronic graft-vs-host disease. After the presentation, I felt that this was very promising.

Transcript edited for clarity.

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