Treatments for Steroid-Refractory Chronic GVHD


A summary of the systemic treatment options available for steroid-refractory chronic GVHD.

Case: A 48-Year-Old Man with Chronic GVHD

  • 48-year-old man undergoes myeloablative conditioning followed by matched unrelated donor hematopoietic cell transplant for acute myeloid leukemia w/ tacrolimus + methotrexate as graft versus host disease prophylaxis
    • The donor is a cytomegalovirus seropositive 50-year-old woman with 3 children
  • Day +22, acute GvHD of skin emerged, successfully treated with slow steroid taper
  • Bone marrow testing performed at 6 months and 12 months post-transplant show AML in complete remission
  • 1.5 years post-transplant, new-onset skin changes with hyperpigmentation, lichen-planus and superficial sclerodermatous-like features on lower trunk and lower extremities (not confirmed); 15% BSA involved
  • Prednisone initiated, initial dose 0.5 mg/kg/d (max 10 mg/kg per week), then 4-week taper
  • After 7 days of prednisone, initial improvement in BSA involvement (now 10% to 15%), with no improvement in range of motion, remained stable thereafter on 0.5 mg/kg every other day


Yi-Bin Chen, MD: We’re blessed by advances in our field over the last 2 or 3 years, maybe even 4 years. We’ve had several advances in the approval of agents for chronic graft-vs-host disease [GVHD]. In the past, when patients required something beyond steroids, there was a litany of options, none of which were approved by the FDA. None of the drugs were defined by well-done prospective studies. In 2019, ibrutinib [Imbruvica] was approved for the treatment of steroid-refractory chronic graft-vs-host disease, ushering this new age of novel agents.

Ibrutinib is an oral Bruton tyrosine kinase inhibitor that many of us have had experience with in treating indolent B-cell malignancies. Its development was driven by research done over the last decade, which suggested that for a subset of patients with chronic graft-vs-host disease, the B-cell arm of the immune system, or humeral immunity, was active. Based on the strength of a 42-patient single-arm study published in 2017, which showed around 67% overall response to ibrutinib, it was approved by the FDA. Many of us were surprised that a 42-patient single-arm study was enough to gain regulatory approval, but the responses were impressive. There were a significant number of complete responses, which are rarely seen in chronic graft-vs-host disease. In a long-term study that followed those patients in 2019, the publication showed that a significant portion of those patients had durable responses.

Critics have said that those 42 patients were highly selected based on the criteria needed to enter the study. Nevertheless, certain patients benefit from ibrutinib for the treatment of chronic graft-vs-host disease. The data say that those who respond tend to have a durable response. The real-world activity, when it’s been used in nonselected patients with refractory chronic GVHD, has not been as impressive. Ibrutinib has issues in terms of toxicities, such as diarrhea and muscle spasms. There are also some cardiac effects. It adds a cumulative immunosuppression as well as a predisposition to bleeding and bruising. It’s been less impressive the more we’ve used it in real-world publications, but it remains an option.

Belumosudil [Rezurock] was approved recently for the treatment of chronic graft-vs-host disease that has failed 2 regimens. This is an oral inhibitor of the ROCK2 kinase, which is thought to participate in the pathway leading to tissue fibrosis. This is moving away from cumulative systemic immunosuppression for chronic graft-vs-host disease, which many of us have cheered and supported. This targets the pathological hallmark of chronic graft-vs-host disease, which is fibrosis or scarring. Belumosudil was approved based on the ROCKstar Study, which was a phase 2 randomized study of 2 different doses. If you look at the entire study, which was over 120 patients, there was over a 70% overall response rate. This can be regarded as a single-arm study because there’s no placebo or other control.

Patients did have impressive responses by the NIH [National Institutes of Health] criteria, and many of us are using it routinely in our algorithm to treat chronic graft-vs-host disease. We’ve been impressed with the responses. It appears from our limited experience to be a very safe drug. A subset of patients have elevations in muscle enzymes or liver function tests, but the vast majority tolerate this agent very well. We await the real-world publications to understand large population experiences in chronic graft-vs-host disease.

The most recently approved agent is probably the most popular in terms of use, which is ruxolitinib [Jakafi]. Ruxolitinib has been around for many years. It’s an oral JAK1/JAK2 inhibitor. Many of us have had experience with it because it had been previously approved for the treatment of myeloproliferative neoplasms. In 2017, it was approved for the treatment of steroid-refractory acute graft-vs-host disease. Many of us had already been using it for chronic graft-vs-host disease because of our own anecdotes and access to the agent.

Then the REACH3 study was published in 2021, which was a large randomized trial with over 300 patients. Randomized trials are quite rare, but this is a phase 3 prospective randomized trial in steroid-refractory chronic graft-vs-host disease comparing ruxolitinib with the control. The control was the best available therapy. That has been criticized, but there has been no other way to do the trial given there was no international accepted standard. Providers were able to pick—from a menu of different options—agents for chronic graft-vs-host disease, including ibrutinib, and compare them with ruxolitinib. For the primary end point, there’s a 6-month overall response rate, and patients in their ruxolitinib arm had an overall response of over 49%; patients in the best-available-therapy arm had an overall response of about 25%. Based on those data and benefits and a failure-free survival of 18 months vs 6 months, ruxolitinib was the most recent agent approved for chronic graft-vs-host disease that has failed steroids.

Those are our conventional approved options in the novel therapy arena. Many of our patients still require other therapies, and we still have older therapies that we formerly used. The only ones that are common these days would be ECP [extracorporeal photopheresis], which has a lot of data behind it. It’s logistically heavy and a tough lift for our patients to undergo in terms of the time they have to spend at the center receiving such therapy. Some of us still use the anti-CD20 antibody rituximab for targeting the B-cell arm that we talked about. There are oral options that some of us use, including sirolimus [Rapamune] and mycophenolate [Myfortic]. Those are the main options we have at our disposal to treat chronic graft-vs-host disease. The approval of the novel therapies ibrutinib, belumosudil, and ruxolitinib has certainly been a huge advance. At the same time, none of these agents are home runs. We need more effective and safe therapies for our patients.

Transcript edited for clarity.

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Yi-Bin Chen, MD, an expert on GVHD
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