Inside the Clinic: Updates in Diagnosis, Treatment, and Management of Chronic Graft-Versus-Host Disease - Episode 11

Selecting Second-Line Therapy for Chronic GVHD

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Shared insight on how best to select ibrutinib, belumosudil, or ruxolitinib for patients with steroid-refractory chronic graft-vs-host disease.


Yi-Bin Chen, MD: Excitingly, we now have 3 agents approved in steroid-refractory chronic graft-vs-host disease [GVHD]. It started several years back, when ibrutinib, the oral BTK [Bruton tyrosine kinase] inhibitor, was approved targeting the B-cell pathway, humeral immunity, and chronic graft-vs-host disease. In 2021 we had approvals from belumosudil, the ROCK2 kinase inhibitor, as well as ruxolitinib. Their labels differ slightly. Ibrutinib is approved only in adults, patients 18 or older, for second-line therapy after steroids. Belumosudil is approved for patients 12 years and older, but it was studied only in patients who had failed 2 lines of therapies. It’s approved for third-line therapy in chronic graft-vs-host disease, and ruxolitinib is also approved for patients 12 years or older but in second-line therapy. If you’re a patient on steroids who needs another agent, ruxolitinib and ibrutinib would be the standard second-line agents available, and then belumosudil as third-line therapy. We look forward to figuring out how to sequence these drugs and how to use them in combination. There’s a lot of work to be done.

Haris Ali, MD: They’re all small molecular kinase inhibitors, and they’re all orally administered. That’s a good thing about them. When I’m choosing a drug for various patients, I find ruxolitinib to be more universal and can be given to any patient as a first line after failing steroid. For ibrutinib, I would avoid using with older patients because of the cardiovascular risk, including atrial fibrillation and bleeding risk. I use belumosudil in patients who have failed both these agents.

Corey Cutler, MD, MPH, FRCPC: What’s fantastic about our 3 second-line and beyond choices in chronic GVHD is that they all work through very different mechanisms of action. Chronic GVHD is clinically and pathobiologically a heterogeneous process. We don’t know which patients might have a dominant pathway in the B-cell side vs a dominant driver in the monocyte-macrophage lineage or a dominant driver in T cells. For that reason, having 3 drugs in second line and beyond that work with varying mechanisms of action is important. We use these drugs relatively interchangeably. We tend to choose them based on the situation of our patient. For example, we try to avoid ruxolitinib in patients who are cytopenic, we avoid belumosudil in patients with very high elevations in bilirubin, and we avoid ibrutinib in patients who have preexisting cardiac conduction defects. We have to take that into consideration.

We also sometimes choose the agent based on the presence or absence of certain clinical features of chronic GVHD. I tend to reach for belumosudil in patients who have sclerotic or fibrotic manifestations of their chronic GvHD, and perhaps ibrutinib in patients with more inflammatory signs of their GVHD. We use factors like that in deciding which agent is right for a given patient. Most often it’s an educated guess at best, but we use toxicity to help influence that decision.

Transcript edited for clarity.