Case 2: Ruxolitinib for Steroid-Refractory Acute GVHD

Corey Cutler, MD, MPH, FRCPC: I think first it is important to talk about definitions, and there are definitions of steroid refractory or steroid resistance. Those typically are related to the timing: individuals who progress while on steroid therapy after 3 or more days, individuals who fail to improve after 5 to 7 days of steroids, and patients who don’t have a complete response after. It says here 28 days, but most of us use a shorter time interval—would be considered steroid refractory. Then, as Usama mentioned before, there is this scenario of steroid dependence during which you can obtain a clinical response, but you are unable to taper the steroids off completely.

There are several variations of these definitions, but on this slide here, we have the standard endovenous laser ablation therapy, National Institutes of Health, and Center for International Blood and Marrow Transplant Research definitions of steroid responsiveness. These are the steroid definitions that most of us use in the context of clinical trials. Having this standard set of response criteria makes it easy for us to enroll patients in a uniform manner across studies.

There are many agents that we use in clinical trials and outside of clinical trials. The slide here demonstrates a list of agents that have been and are currently considered the standard of care in this scenario, and I would emphasize more than anything that the most important agent on this slide is called the clinical trial. Because, particularly in patients with steroid-refractory disease where outcomes are poor, clinical trials still are our mainstay of therapy.

I am going to talk about 1 agent in particular, and the reason to single out ruxolitinib in this scenario is because ruxolitinib was recently approved as a therapeutic for steroid-refractory acute graft-versus-host disease [GVHD]. It was approved on the basis of the single-arm, open-label, phase 2 REACH1 study. More recently, the REACH2 study was published in the New England Journal of Medicine by Robert Zeiser, MD, and colleagues. REACH2 was a randomized phase 3 trial, and slightly over 300 patients were randomized in this study to receive either ruxolitinib or the best available care. In this trial, there were 9 regimens that were considered acceptable for investigators to use for patients who were not randomized to the ruxolitinib arm.

The primary end point of this study was the overall response 28 days after starting the second-line therapy. This graph demonstrates the significant improvement in overall response rate to slightly over 60% in the ruxolitinib arm in comparison to slightly under 40% in the control arm. Again, large sample sizes, very significant P value, both statistically significant but also clinically very significant, I would say, with an increase in more than 20% response rate at day 28.

The secondary end points of this trial looked at the durability of response at day 56. Again, here we see an increase in the durability, nearly double, from 21.9% to 39.6%, comparing the control and the ruxolitinib arms. Beyond day 56, the rate of losing response toward 6 months was also much lower. It was only 10% in the ruxolitinib arm, so this, in fact, was more supporting evidence. Finally, the Kaplan curves here show failure from survival with a very nice, clean increase in the ruxolitinib arm compared to the control.

The investigators showed that, as one would have predicted, there was a significant rate of cytopenia in this trial. Nearly a third of patients had either thrombocytopenia or significant anemia, but, very importantly, there was not an increased rate of infections; it stands to be said that infections are a major cause of morbidity and mortality for patients with steroid-refractory acute GVHD.

Transcript edited for clarity.