Disease Site and Access Factor into Selection of GVHD Therapy

Catherine J. Lee, MD, MS

Associate Professor
Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, WA

DISCUSSION QUESTION

• What is the significance of the different mechanisms of action of the approved therapies for chronic graft-vs-host disease (GVHD)?

Catherine J. Lee, MD, MS: Ibrutinib [Imbruvica] is a Bruton tyrosine kinase inhibitor used in chronic lymphocytic leukemia and other lymphomas. It can also target the T-cell pathway, which is great in chronic graft-vs-host disease [cGVHD], because we know that both the B- and the T-cell pathways are involved in cGVHD. It targets the IL-2–inducible T-cell kinase. Ibrutinib abrogates B-cell signaling that's important for B-cell survival, proliferation, and migration. That leads to the development of the allo-antibodies that we know are active in cGVHD, and then, because it targets a T-cell pathway, it also mitigates T-cell activation, cytokine release, and proliferation.¹

Belumosudil [Rezurock] is a ROCK2 inhibitor. ROCK2 inhibition rebalances the immune response to treat immune dysfunction, and ROCK regulates multiple profibrotic processes, including myofibroblast activation. ROCK2 inhibition decreases collagen deposition and diminishes the activation of the profibrotic genes. Initially, when belumosudil came out, we knew more of its antifibrotic properties, and so it was marketed as being an antifibrotic agent, but we know now that it has potent anti-inflammatory activities. We shouldn't disregard the anti-inflammatory properties of belumosudil.

Many of us use ruxolitinib [Jakafi] to treat myelofibrosis and other myeloproliferative diseases, but it is a great drug for cGVHD because of its highly immunosuppressive activity through the inhibition of JAK/STAT signaling. It blocks T cell activation and blocks cytokine activation, is involved in upregulating T regulatory cells, and decreases collagen deposition.

Lastly, axatilimab [Niktimvo] has a novel mechanism of action. It is a CSF1 receptor inhibitor. [In terms of] pathophysiology, the colony–stimulating factor 1 is a ligand that promotes the growth and differentiation of donor-derived monocytes into macrophages. These monocytes and macrophages have proinflammatory and profibrotic mechanisms, so blocking the activation of the receptor depletes the donor derived macrophages and abrogates cGVHD in that mechanism.

DISCUSSION QUESTIONS

• What are the key factors that drive your decision making? ​
• Does a specific organ involvement such as lung, gastrointestinal tract, or genitourinary tract change your treatment approach?

Basel Shoua: Ruxolitinib is category 1 preferred in the NCCN guidelines.² I feel comfortable using it, and I have seen the outcome of using it for skin manifestation in GVHD was almost complete resolution of the patient's skin manifestation.

Lee: I agree. [The REACH3 trial (NCT03112603)] was the only randomized trial that compared ruxolitinib against best available therapy, so it has the strongest data or the [most] optimal clinical trial design. In addition to seeing responses in the skin, there are reports that ruxolitinib seems to be effective for oral GVHD, and I think that is something that the providers at Fred Hutchinson Cancer Center are seeing as well. I know that many of us like to use ruxolitinib for oral GVHD.

What about skin sclerosis? Would any of you try to use belumosudil before ruxolitinib if insurance was not an issue? Do any of you have a feeling that belumosudil is better for fibrotic manifestations, or do you feel that it could be just as efficacious for the inflammatory manifestations?

Bramham Reddy, MD: I don't have much knowledge about [belumosudil], but since we as medical oncologists are now so familiar with ruxolitinib, I think we'll go with the drug that we're familiar with before we try...the other drug.

Warren Alperstein, MD: I've had great experience and a great response with the ROCK inhibitors for cGVHD in the skin, but the biggest thing is, I don't think I've ever got it approved in the front line before I've tried ruxolitinib.

Lee: You haven't tried belumosudil up front?

Alperstein: Not before ruxolitinib. The insurance companies will dictate how [I use it]. But I've had patients respond very well, and sometimes, if I think it's going to work, if a patient's been on ruxolitinib for a week or 2 and hasn't responded, I say I'm switching. [I would] not give ruxolitinib [another] chance if they have bad sclerosis; sometimes I will switch sooner than later. But I've seen patients respond nicely.

Lee: Axatilimab is an intravenous [IV] infusion. For those who are not in large academic center, do you think you might have axatilimab at your oncology practice? Do you know if it's being attempted to get on formulary? I think that's going to be one of the interesting things when axatilimab is available, between belumosudil and axatilimab in the third-line setting or beyond. For patient convenience, belumosudil is a pill, and I can see that patients might prefer that, whereas axatilimab is an every-2-week IV infusion, and probably at the very beginning it's only going to be available at the large treatment centers.

Eventually, to make it more accessible for patients, axatilimab has to be available at community oncology centers, similarly to rituximab [Rituxan] and other monoclonal antibodies that are used in solid tumors. That is something to keep in mind.

_{DISCLOSURE: Lee previously reported advisory board participation for Sanofi, Kite, Kadmon, BMS, and Incyte; research funding from Incyte; steering board committee participation for Incyte; speakers panel participation for Kite; and consulting for Fresenius Kabi, Sanofi, and Mallinckrodt.}

_References:

_{1. Buxbaum NP, Socié G, Hill GR, et al. Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD. Blood Adv. 2023;7(17):4886-4902. doi:10.1182/bloodadvances.2022007611}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic Cell Transplantation, version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf}