The best practices for treating patients with steroid-refractory chronic graft-vs-host disease, with implications for using ruxolitinib based on results of the REACH3 clinical trial.
Parameswaran Hari, MD, MRCP: Let’s talk about the agents that are used to control chronic GVHD [graft-vs-host disease]. The first-line therapy is corticosteroids, and then we go to the approved agents. At this time, we have at least 3 other approved agents. Extracorporeal photopheresis has been around for a long time. We don’t think of it as an agent, but it’s a technology that’s used and specifically approved for chronic graft-vs-host disease. We have recent approvals for 3 drugs in the chronic graft-vs-host disease setting: ibrutinib [Imbruvica], belumosudil [Rezurock], and, most recently, ruxolitinib [Jakafi].
It’s important to distinguish steroid-refractory chronic GVHD from steroid-sensitive chronic GVHD. A lot of time, we use steroids with another drug that’s thought as a steroid sparer in that setting. We’ll get into the nuances of all that and some of the studies in a second, but let‘s first go to the next audience polling question. What is your definition of steroid-refractory chronic graft-vs-host disease? Symptoms worsening after 3 days of treatments with steroids, symptoms worsening after 7 to 10 days of treatment, symptom flare with tapering of treatment, or other? This question is specifically for chronic GVHD.
The majority of people have said symptoms worsening after about 10 days of treatment. Symptoms flaring with treatment, tapering of treatment, and a very small minority have chosen 3 days. It’s more of a practice definition, but I tend to think of it as progressive disease if there’s at least 2 weeks of a fairly good dose of steroids—at least 1 mg/kg—in terms of the chronic GVHD setting, or patients who haven’t adequately responded after about 4 weeks of steroids. Nelson, if we’re unable to taper steroids below 50% from the starting dose, maybe 0.5 mg/kg, how do you think of steroid-refractory chronic GVHD?
Nelson J. Chao, MD, MBA: I’d agree with that. You can’t see much in 3 days. It’s not like acute GVHD. Two weeks is probably the lower limit of waiting. Some of the symptoms are by virtue of it being chronic. They’ve had this for weeks and months. Things might not turn around that quickly, so I tend to look between 2 to 4 weeks.
Parameswaran Hari, MD, MRCP: Absolutely. Let’s move on to the most recently approved medication for steroid-refractory chronic graft-vs-host disease: ruxolitinib. Yi-Bin, you were an investigator on the REACH3 trial. Would you like to talk a little about the mechanism of action of ruxolitinib and the practical benefit and offer tips on using this agent for steroid-refractory chronic graft-vs-host disease?
Yi-Bin Chen, MD: First, I’ll say that just like how you had mentioned with acute GVHD, we rarely see large phase 3 prospective randomized trials in steroid-refractory chronic graft-vs-host disease either. So praise and applause go out to the community at large to conduct that trial, even though the control was the best appropriate therapy, which is a bit utter genius. I’m not sure how a better control could have been selected. It’s really gratifying to see phase 3 trials completed to show a difference and make progress in the field.
I’m not sure we truly know exactly how ruxolitinib works, but it inhibits the JAK1 and JAK2 kinases and they’re downstream in several inflammatory cascades. It has broad anti-inflammatory actions. You see this a lot when you treat someone with myeloproliferative disease who has systemic symptoms, where you give them ruxolitinib and it just shuts it down. But we obviously think these pathways are vital in the alloreactivity cascade as well as in the sustainability of these immune responses. There’s also clear evidence from mouse models that these pathways are important for lymphocyte trafficking to get to the actual place they need to go to sustain their activity and so forth. That’s how we view it works as a broad anti-inflammatory agent. We tend to think it’s not as immunosuppressive as our agents of the past, but it’s not tax-free. There’s some immunosuppression to it.
You had mentioned before that in acute and chronic graft-vs-host disease, at least in our experience, the main adverse effects of ruxolitinib are hematopoietic. Hitting the JAK2 pathway, that‘s downstream from signaling for EPO [erythropoietin] and TPO [thrombopoietin], so if you see a subset of patients who develop significant anemia or thrombocytopenia, that requires dose adjustments or even stopping the drug itself.
Transcript edited for clarity.