Phase 2 REACH1 Overview

Usama Gergis, MD: In this case, we have a patient with corticosteroid-refractory acute graft-versus-host disease [GVHD] who was not responding to the first-line treatment of prednisone 2 mg/kg, or the equivalent. There are many treatment options. This patient’s case is more complicated because he has 3-fold involvement. Historically, photopheresis works well for skin graft-versus-host disease. If the patient only had skin graft-versus-host disease, I would probably start him on photopheresis. Liver and GI [gastrointestinal] disease can be more resistant to this. So, the best option for him at this point would be ruxolitinib [RUX] and he was appropriately started on this drug.

The REACH1 trial was the phase 2 multicenter trial that led to the approval of ruxolitinib in patients with corticosteroid-refractory acute graft-versus-host disease. Whenever I say refractory, I also imply steroid-dependent. As I said earlier, the prognosis, the treatment, and survival is the same. The trial was a phase 2 multicenter trial with inclusion criteria of patients with steroid-refractory or steroid-dependent acute graft-versus-host disease. This trial studying graft-versus-host disease enrolled 71 patients who were followed for adverse effects. However, only 49 patients were followed for efficacy, as about 22 did not qualify for the efficacy follow-up. These patients either had other lines of therapy not including steroids before starting the ruxolitinib or they were not optimized on steroid treatment. The primary end point of the trial was an overall response rate at day 28. Other end points included similar trials, duration of response, degree of response, SAEs [serious adverse events], and others.

Ruxolitinib was studied in patients with acute graft-versus-host disease because ruxolitinib is a JAK/STAT pathway inhibitor. The JAK/STAT signaling pathways help to regulate the development of proliferation in immune types important for graft-versus-host disease. So, the signaling of proinflammatory cytokines, the activation of cytotoxic T cells, the separation of regulatory T cells—all these mechanisms are JAK/STAT dependent. If you block this very important acute GVHD pathway, you probably can help with acute GVHD. And that’s basically the background of using RUX in this arena.

Transcript edited for clarity.

Case Overview:

Initial presentation

• A 61-year old man presented with a generalized pruritic rash, abdominal pain and diarrhea (8-12 BMs/day)
• PMH: he underwent haploidentical allogeneic hematopoietic-cell transplantation for AML 40 days ago
• PE: maculopapular erythematous rash on bilateral palms, cheeks, ears and upper back (rash involvement >50% of skin); abdomen is tender to palpation diffusely
  
  

Clinical workup

• Labs: ANC 0.7 x 109/L, plt 75 x 109/L, total bilirubin 8 mg/dl, AST 54 U/L, ALT 60 U/L
  • Negative for HBV, HBV, CMV, EBV, HHV-6
• Negative stool tests
• Flexible sigmoidoscopy with biopsy:
  • Lower GI biopsy showed moderate mixed inflammation in the lamina propria and scattered apoptotic bodies without crypt loss
• Skin punch biopsy of the back shows hyperkeratosis, hypergranulosis associated with lichenoid inflammatory infiltrate
• Modified Glucksberg criteria: grade 3; MAGIC criteria: grade III
  
  

Treatment

• Systemic corticosteroids (prednisone 2 mg/kg/day) + topical steroids (triamcinolone)
  • No treatment response after day 5
• He was started on ruxolitinib 5 mg PO BID, increased to 10 mg PO BID on day 6