Deciding When and How to Add Therapy for Steroid-Refractory GVHD

After patients are diagnosed with chronic graft-vs-host disease (GVHD), they may receive systemic corticosteroids as a first line of therapy, but stable disease or progression is indicative of steroid refractoriness. In a virtual Case-Based Roundtable event for physicians in the central US, Michael R. Bishop, MD, director of the Hematopoietic Cellular Therapy Program, director of the David and Etta Jonas Center for Cellular Therapy, and professor of medicine at the University of Chicago, discussed how to approach steroid-refractory GVHD. One of the treatments Bishop examined was belumosudil (Rezurock), which was investigated in patients who had been treated with prior approved therapies and yielded results showing distinct organ-specific responses.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

CASE SUMMARY

• A 48-year-old man underwent a myeloablative conditional matched unrelated donor hematopoietic cell transplant for acute myeloid leukemia (AML) with tacrolimus plus methotrexate as GVHD prophylaxis​.
• The donor was a 50-year-old woman with 3 children who is seropositive for cytomegalovirus.
• After day 22, acute GVHD of the skin emerged and was successfully treated with slow steroid taper​.
• Results from bone marrow biopsy performed at 3 months post transplant showed AML in complete remission​.
• He returned at 6 months post transplant with normal blood counts. He presented with skin changes with hyperpigmentation, with approximately half of each arm showing lichen planus; superficial sclerotic features (able to pinch the skin) on the lower trunk and lower extremities; 18% body surface area involved; and no decrease in forced expiratory volume in first second of expiration/diffusing capacity of the lung for carbon monoxide on pulmonary function test results.
• Prednisone initiated, initial dose 0.5 mg/kg/day, then 4-week taper.​
• After 7 days of prednisone, initial improvement in body surface area (BSA) involvement​.
• Patient received taper; however, increase in BSA involvement from 15% to 20% during prednisone taper​.
• A subsequent taper was attempted unsuccessfully​.
• Symptoms remained stable thereafter on 0.5 mg/kg every other day.

Targeted Oncology: What are your thoughts on the options in this case?

Michael R. Bishop, MD: The first [option] is to monitor patient disease, and if it remains stable to maintain the steroid dose. The involvement of a new organ would be considered steroid refractory. The second is to monitor the patient and increase steroid dose, or the third is to increase steroid dose. Going to a higher dose than 1 mg/kg is not shown to significantly change outcomes in these patients. By definition, the patient has steroid-refractory GVHD.

The first [option] would be fine clinically; you could [monitor] for another week or 2 to how they’re doing, but also because they do meet the criteria for steroid refractory, immediately going to another agent [could be done]. There is evidence that the earlier that you intervene when you have steroid-refractory [GVHD], the greater chance you’re going to have a success in preventing further organ progression and more success in terms of outcomes by intervening earlier.

What treatment options could be used for a patient with steroid-refractory chronic GVHD?

Our options would be a clinical trial or adding additional agents.¹ Ruxolitinib [Jakafi] is considered a category 1 for steroid-refractory GVHD. We have 3 other FDA approved agents. We have ibrutinib [Imbruvica], which was the first FDA-approved treatment for chronic GVHD. We have belumosudil, and most recently, we have axatilimab [Niktimvo].

Some alternative agents which have been used [include] pentastatin, a relatively old [treatment] that could wipe out T cells, but we subsequently learned it can be B-cell mediated. Rituximab [Rituxan] became popular for a while. There was a nice paper from Dana-Farber Cancer Institute on using IL-2.² You wouldn’t think about IL-2 being the best drug to use, because it stimulates T cells, but T cells exhaust, so you use low-dose IL-2 continuously, and eventually you might get a bit of a flare, but theoretically, the T cells should exhaust themselves. Another very popular one is extracorporeal photopheresis. All of these have been used in various degrees.

What findings support the use of belumosudil in chronic GVHD?

ROCKstar [NCT03640481] had very similar eligibility criteria [to REACH3 (NCT03112603)], although this only allowed adults. Patients had to have 2 or more prior therapies, but it did limit it to 5 lines of systemic therapy whereas REACH3 allowed [as many as] 13 different drugs. This is a phase 2 study, and they looked at 2 different dosing of belumosudil. Patients either could get 200 mg once a day or 200 mg twice a day.

The primary end point was overall response rate [ORR], and they wanted to see over 40% ORR, and they got 74% with belumosudil once a day vs 77% with it twice a day.³ Based on that, because it is easier to take and has fewer adverse events, they approved the once-a-day dosing.

What was the organ involvement among the patients treated in this trial?

In terms of organs involved, joints were [involved] in 75%, skin in about 80%, and about [75%] in the eyes. I think it’s important to see where what the organs are involved, but this would be what we would typically see with chronic GVHD. The incidence of severe chronic GVHD was 70%, and it does include one-third of patients who had prior ruxolitinib and about one-third of patients who had prior ibrutinib. Now we’re seeing 2 of the FDA drugs; in REACH3 you had a choice of ibrutinib, but now here are some patients with ruxolitinib. [GVHD was] extensive with 4 or more organs [involved] in about half the patients.⁴

What stood out among patients who responded to belumosudil?

Even if the patients had prior ruxolitinib, there was a good response rate [68%] and with ibrutinib, there was a good response rate of 74% The number of prior therapies didn’t make any difference. The number of organs involved didn’t make any difference, although it’s even a bit better in patients who had less than 4 organs involvement. All of the [subgroups] fall within the confidence interval, so there was no specific group that was either better or worse. In terms of Lee symptom score, 60% felt better, and that’s defined by at least a 7-point decrease in the Lee scale. Nearly two-thirds of patients could have their steroid taper, 1 in 5 got off corticosteroid, and 1 in 5 stopped the additional agents they were on.³

When we look at organ response, this is where I think it’s important. If we look at joints and fascia, there was a high response rate of 71%; only 20% had a complete response. When we look at lower [gastrointestinal (GI) symptoms], 69% and a 60% complete response rate. In the upper GI it was about 52%. In the mouth it was 55%; in skin, 37%; in the eyes, 42%; in the liver, 39%; and in the lungs, 26%. These are not unexpected. With ruxolitinib, they tend to have higher [response rates in] skin and eyes. That’s what we think about with steroids as improvement. But this joint and fascia improvement and the GI improvement is pretty good; it’s a bit disappointing in terms of lungs and liver, but still improvement in one-quarter and approximately one-third, respectively.

In terms of [other] end points, there was a 2-year failure-free survival [FFS] rate of [nearly] 50% and 3-year FFS rate of 44%. Among responders, FFS rate was 57% and 51%, respectively. There was not much difference in terms of the end points between the 2 doses.⁴

[Looking at] FFS curves…there’s a plateau at the end of 40% when the median FFS is between 18 and 21 months. And then and among responders a little bit higher between 21 and 24 months.

What is the tolerability profile of belumosudil?

In terms of toxicities, there’s one thing to take away: the number 1 cause of death among patients the chronic GVHD is infection. Looking at grade 3 to 4, there was 8% pneumonia. There was hyperglycemia and hypertension, not unexpected.³ Trying to look at cytopenias, one of the advantages here is that relative to ruxolitinib, with belumosudil you’d don’t get significant cytopenias in comparison.

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_{DISCLOSURES: Bishop previously reported research funding from AbbVie, Ascentage, Kite, a Gilead Company, Kura, and Takeda.}

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation, version 2.2025. Accessed September 8, 2025. https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf}

_{2. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055-2066. doi:10.1056/NEJMoa1108188}

_{3. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study. Blood. 2021;138(22):2278-2289. doi:10.1182/blood.2021012021}

_{4. Lee SJ, Cutler C, Pavletic SZ, Blazar BR. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of systemic therapy: 3-year follow-up of the ROCKstar study. Transplant Cell Ther. 2024;30(suppl 2):S262-S263. doi:10.1016/j.jtct.2023.12.349}