Initial, Steroid-Refractory, and Novel Treatment Options for GVHD

Yi-Bin A. Chen, MD:In patients who develop acute graft-vs-host disease, cutaneous disease in the form of a skin rash is the most common presentation we see. In general, we do focus on topical therapy first if the skin rash is limited and patients are able to have enough body-surface area or not too much body-surface area to use topicals. Once it exceeds that or there is visceral organ manifestation, we do move on to systemic steroids. In the literature, you’ll see that the standard dose is 2 mg/kg of prednisone, or a steroid equivalent, on a daily dosage, as either a single dosing or divided into 2. While that’s in the literature and in clinical trials, in daily practice that’s oftentimes difficult to carry out based on patient comorbidities such as performance status, diabetes, osteoporosis, or other reasons. In general, at our institution, if patients have skin-only disease, they’re generally treated with 1 mg/kg of prednisone on a daily basis. If they have liver or intestinal involvement, we do treat with 2 mg/kg per day. Obviously, there are exceptions for patient-specific issues.

Steroid-refractory acute graft-vs-host disease has several definitions. In clinical trials, the traditional definitions have been if patients are getting worse on the initial regimen after 3 days, if they’re not getting better after 7 to 14 days, or if they’ve initially responded and then, upon taper of the steroids, they have a flare of disease. These, as you can imagine, are 3 very different definitions, but they’ve all fallen under the definition of steroid refractory, and that’s 1 reason why trials have been difficult to conduct for this population. We generally move on fairly quickly at our institution to second-line therapy, and we do try to keep to these definitions. If patients are not responding after 3 days, we very quickly move on to a second-line agent. We’ll generally wait only 7 days. If patients are not getting better after 7 days, then we move on to second-line therapy as well. Certainly when patients flare with symptoms upon a taper of steroids, while we do escalate steroids back to the initial dose, we will move on to a second-line agent as well, in order to ultimately spare steroid exposure for that patient.

The approval of ruxolitinib for steroid-refractory acute graft-vs-host disease is a major advance. Currently, it is approved for patients 12 years and older for the treatment of steroid-refractory acute graft-vs-host disease. This approval was based on the results of the multicenter REACH-1 trial. REACH-1 was a single-arm, phase II trial that was conducted in 71 patients with steroid-refractory graft-vs-host disease.

When the FDA looked at the data for approval, [it] identified 49 of those 71 patients as qualifying for its definition of steroid refractory. Of those 49 patients who received ruxolitinib for steroid-refractory graft-vs-host disease, I believe 57% showed an overall response, with 30% of patients having a complete response. That was very compelling, very competitive compared with the historical trials that had been done with other agents. Based on that trial, the FDA approved ruxolitinib for steroid-refractory acute graft-vs-host disease.

All of us in the community treating patients were ecstatic, because we do believe that ruxolitinib has a role in treating acute graft-vs-host disease. Whether it should be the standard for steroid-refractory acute graft-vs-host disease remains controversial. I think it is 1 of the first agents that has been tested in rigorous clinical trials; thus it has been approved. Access to the agent has made a difference for many patients with both acute and chronic graft-vs-host disease. Currently, we do use ruxolitinib as a standard option for patients with steroid-refractory acute graft-vs-host disease and have had a promising experience with it, absolutely.

Ruxolitinib appears to have a role in chronic graft-vs-host disease as well. This has been gathered by anecdotal reports that have been published and based on our own experience. REACH3 is a multicenter, phase III randomized study that is comparing ruxolitinib with best appropriate therapy for patients with steroid-refractory chronic graft-vs-host disease.

Upon enrollment on a trial, when patients have met the definition of steroid-refractory chronic graft-vs-host disease, patients were randomized to either ruxolitinib or best appropriate therapy. Best appropriate therapy was investigator’s choice of several agents defined in the trial that have been standardly used throughout the years for the treatment of steroid-refractory chronic graft-vs-host disease. The primary end point for this trial is overall response rate at 6 months after enrollment. We ultimately hope to see that ruxolitinib is superior to best appropriate therapy in response. Hopefully this will pave the way for the approval of ruxolitinib in steroid-refractory chronic graft-vs-host disease as well.

Transcript edited for clarity.