A review of treatment options approved for steroid-refractory chronic graft-versus-host disease starting with ibrutinib and ruxolitinib.
Nelson Chao, MD:Let’s talk about the treatment options. In general, if it’s mild [graft-vs-host disease], with dry eyes or topical skin changes, supportive treatment is usually enough. If it’s moderate to severe, systemic treatments should be used, like steroids. Based on the NIH [National Institutes of Health] criteria, one waits for response when asked to monitor for infections. Keep in mind, you’re adding immunosuppressants to a patient who’s probably immunosuppressed already by virtue that the patient developed chronic GVHD [graft-vs-host disease]. We talked a little about this earlier, but supportive care is really important in patients: physical therapy, occupational therapy, mental health support, and financial support.
The guidelines from NCCN [National Comprehensive Cancer Network] for steroid-refractory GVHD are listed here. Clinical trials are still No. 1, although there are 4 FDA-approved drugs: ruxolitinib, ibrutinib, and belumosudil. Imatinib was the first to be approved. This was based on a very small study of 38 patients, I believe.
Corey Cutler, MD, MPH, FRCPC: Forty-two, I believe.
Nelson Chao, MD: Forty-two patients. As you can see, there was a reasonable CR [complete response] rate, with an overall response of 69%. Looking at the median corticosteroid dose, the treating physicians felt comfortable enough to be tapering their steroids in terms of the people who responded. This was approved in 2018. The FDA approved ruxolitinib for chronic GVHD in September 2021. This was for patients who failed 1 or 2 lines of therapy—adult and pediatric patients 12 years or older.
I want to go over the phase 3 REACH3 study. This was a large, randomized study of 329 patients who were stratified by their chronic GVHD grade. They had a lack of response and progressive disease after 1 mg/kg for 1 week, or 0.5 mg/kg for 4 weeks, or an increase of the prednisone dose of more than 0.25 mg/kg after 2 unsuccessful attempts to taper. They had to have myeloid and platelet engraftment. They’re randomized into the ruxolitinib, with steroids plus or minus the calcineurin inhibitor, or the best alternative therapy. The first primary end point was at week 24, looking at overall responses. The secondary end point looked at failure-free survival substitute. There was a similar design for the GVHD. It was ruxolitinib compared with the best alternative therapy. Those were selected by the investigators and included ECP [extracorporeal photopheresis], low-dose methotrexate, MMF, mTOR inhibitors, infliximab, rituximab, pentostatin, and imatinib.
There was an extension period up to week 156. These data show that about half the patients had an overall response by week 24. Overall responses were great. Complete responses were relatively few. The best overall response ended up being about 76% for ruxolitinib and about 60% for the best alternative therapy, so it looked like all organs responded. The patients who crossed over—there were 61—also had a response similar to what one saw with the ruxolitinib up front.
This [chart] is for failure-free survival. You can see the ruxolitinib curve, at a robust failure-free survival, compared with the control arm with a hazard ratio of 0.37. The duration response was also better with ruxolitinib compared with the control, with a duration of response not reached on a ruxolitinib mark.
We didn’t talk about this in the acute setting, but ruxolitinib clearly has adverse events. Most of the adverse events are hematologic, with an increase in anemia, thrombocytopenia, neutropenia. Not surprisingly, these are the adverse effects of the drug. Outside that, it wasn’t terribly different in many of the other adverse effects that it had when compared with the control.
Transcript edited for clarity.