The REACH2 Study in Steroid-Refractory Acute GVHD
Dr Michael Bishop, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago, describes the rationale for the design of the phase 3 REACH2 trial in steroid-refractory acute graft-versus-host disease and provides perspective on important takeaways from data presented.
Michael Bishop, MD: The REACH2 study, which was published in The New England Journal of Medicine by Robert Zeiser, MD, et al, was an international, multi-institutional trial of patients with steroid-refractory acute graft-versus-host disease using the criteria that I described before. Patients were randomized to receive either ruxolitinib or investigator’s choice. The FDA approval for ruxolitinib in the United States allows ruxolitinib to be started right off the bat at 10 mg twice a day. This is based upon REACH1, where they started at 5 mg twice a day, and then, if a patient was tolerating it well you could go up to 10 mg twice a day, if your blood cell counts were fine after 3 days on treatment. Again, in this study, patients got randomized to ruxolitinib, 10 mg twice a day, or the investigator’s choice. The investigator’s choice included sirolimus, extracorporeal photopheresis, mycophenolate mofetil, as well as a number of anti-inflammatory cytokines. And so, they could use any one of these as part of treatment. That was how the study was designed. The end point was response after 56 days on treatment.
What the study demonstrated very significantly is that there was significant organ improvement in grade 2, 3, and 4 disease. Then they randomized patients according to grade of their graft-versus-host disease. What is demonstrated also was it didn’t depend which organ was involved. If you looked at patients who had hepatic involvement, which we all think of as being the worst and the hardest to treat, the ruxolitinib arm was superior in terms of response in liver involvement versus the investigator’s choice arm. That was also seen for GI [gastrointestinal involvement]; it was also seen for skin. When we’re treating graft-versus-host disease, the best response is typically seen with the skin. The second best response is seen in the gut, and the worst is seen in the liver. Yet we saw a significant improvement on the ruxolitinib arm compared to the control arm in every single organ, in every single grade.
The overall response rate in grade 2 graft-versus-host disease on the ruxolitinib arm was between 70% and 75%. In grade 3 graft-versus-host disease, if I’m correct, the overall response rate on the ruxolitinib arm was about 40% to 45%. The impressive thing is that even in grade 4 graft-versus-host disease, ruxolitinib had about a 40% response rate. I think that’s impressive because, as I mentioned before, as you go to a higher grade, the response rate with conventional therapies tends to go down. Yet, response to ruxolitinib therapy was pretty similar in grade 3 and grade 4 disease. As I mentioned, in all 3 situations ruxolitinib was superior to the investigator’s choice of treatment in terms of response.
Transcript edited for clarity.
Case: A 53-Year-Old Man With Steroid-Refractory Acute Graft-Versus-Host Disease
Initial presentation
- A 53-year-old man presents on day +40 for a routine follow-up visit after matched donor peripheral blood stem cell transplant. He complains of a new rash, abdominal pain and ‘countless’ loose stools every day for the last 4 days
- PMH: unremarkable
- PE: Rash noted on arms and upper trunk (~45% BSA); diarrhea was quantified to about 1100 cc/day
Clinical workup
- Labs: total bilirubin 2.6 mg/dl, AST 60 U/L, ALT 75 U/L, Hb 9.8 g/dl
- Negative for HBV, HBV, CMV, EBV, HHV-6
- Stool testing negative for bacterial/viral infection
- Skin biopsy of the rash showed exocytosed lymphocytes, and dyskeratotic epidermal keratinocytes with follicular involvement
- Colonoscopy with biopsy showed numerous apoptotic bodies in the crypt epithelium
- He was diagnosed with acute GVHD:
- Skin stage 2
- GI stage 2
- Liver stage 1
- Modified Glucksberg Criteria: grade II; MAGIC Criteria: grade II
- ECOG 1
Treatment
- Initiated methylprednisolone 1.0 mg/kg and topical steroids
- There was minimal response to treatment after 2 days, dose was increased to 2.0 mg/kg/day
- Continued on systemic steroids for 5 more days; rash subsided minimally
- He was started on ruxolitinib 5 mg PO BID, tolerated well; increased to 10 mg PO BID at day 3
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