Steroid-Refractory Acute Graft-Versus-Host Disease Defined

EP: 1.Case Assessment: 53-Year-Old With Steroid-Refractory Acute GVHD

EP: 2.Acute Graft-Versus-Host Disease: Diagnostic Criteria & Prevention

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EP: 3.Steroid-Refractory Acute Graft-Versus-Host Disease Defined

EP: 4.Acute GVHD: Assessing Response to Steroid Therapy

EP: 5.The REACH2 Study in Steroid-Refractory Acute GVHD

EP: 6.Using Ruxolitinib to Treat Steroid-Refractory Acute GVHD

EP: 7.Managing Acute GVHD in Community Settings

Michael Bishop, MD: How do we define steroid-refractory acute graft-versus-host disease? This was developed through a consensus conference between the NIH [National Institutes of Health], CIBMTR [Center for International Blood and Marrow Transplant Research], and EBMT [European Society for Blood and Marrow Transplantation]. They defined steroid-refractory as patients who were generally receiving a 2 mg/kg dose of methylprednisolone or equivalent. If the disease progressed after 3 days of being on high-dose methylprednisolone, that defined the patient as having steroid-refractory graft-versus-host disease.

Another definition of steroid-refractory graft-versus-host disease is that you’re on that high-dose methylprednisolone for at least 7 days and you don’t see any improvement. That’s the second criterion that meets the definition of steroid-refractory graft-versus-host disease.

The third criterion that would meet that definition is if a patient did initially respond to that high-dose methylprednisolone, but when you attempted to taper, you could not get them down to start the taper, they required prolonged high doses of methylprednisolone. That would also meet the criteria for steroid-refractory graft-versus-host disease.

What would trigger me to escalate the dose or make a change in treatment? I may do so if I see a certain stage of disease is progressing. For instance, if I initially had a stage 2 patient being treated with high-dose steroids, and they progressed to stage 3 or stage 4. Or similarly, if I started out with a patient with stage 2 disease of the gut, and all of a sudden the frequency and the stool volume was increasing, and I wasn’t seeing any response to steroids, that would lead to a dose escalation. Like our case presentation, if they were being treated with 1 mg/kg, I would potentially raise the dose to 2 mg/kg. If I didn’t see a good response after just a few days, then I would be thinking of turning to alternative treatments.

In regard to the treatment options available, in the first-line setting I’m thinking about ruxolitinib, which is FDA approved in this situation. A phase 3 trial compared ruxolitinib to dealer’s choice, as they say. This was left up to the investigators. They had about 9 treatments they could choose from. In the study, ruxolitinib did demonstrate significant organ improvement for patients who had steroid-refractory acute graft-versus-host disease. In many of these cases, patients’ corticosteroid doses were tapered. That would really be the same approach if I saw progression or no response after 2 to 3 days, or a lack of response after a week of therapy.

Most of the time, for grade 2 patients we’re looking at the skin. This depends upon the patient’s performance status and how they are doing. If I saw that the patient’s performance status was declining, for grade 2 disease I’m going to be a bit more conservative with treatment. I may try to give other treatments. I might give the steroids a bit longer to work, as long as the patient looked clinically stable. But if I was still not seeing any good response to grade 2, I would think about adding ruxolitinib because I feel comfortable adding that drug.

When I get to grade 3 disease, if I’m not seeing good response early, within that 7-day window, I’m thinking about using ruxolitinib right away. And when I get to grade 4 acute graft-versus-host disease, I’ve already started thinking about ruxolitinib. If I’m seeing a patient with grade 4 disease, I know that the mortality rate is high, so I’ll think about adding another form of therapy along with ruxolitinib and steroids. Most of the time, I’m thinking about adding extracorporeal photopheresis.

With ruxolitinib, the median time to response is pretty good, so you’re hopefully going to see a response within 7 to 14 days. It’s not always that early, but the median time is right around there. No matter what, I’m already trying to think about what I am going to be using next to help me try to get this patient’s graft-versus-host disease under control.

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