Defining Steroid Refractory aGvHD

EP: 1.Case Overview: Steroid Refractory aGvHD

EP: 2.Predictive Prognosis and Risk-Stratification in aGvHD

EP: 3.Clinical Risk Factors and Prophylaxis for aGvHD

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EP: 4.Defining Steroid Refractory aGvHD

EP: 5.Treatment Options for Steroid Refractory aGvHD

EP: 6.Unmet Needs in the Management of aGvHD

Yi-Bin Chen, MD: There have been several definitions of steroid-refractory acute graft-versus-host disease that have been used throughout the years and for clinical trials. They can be separated into 3 categories.

Everyone would agree that after 3 days of high-dose systemic steroids, if your patient is getting worse, that meets the definition for steroid refractory. Another definition is just not getting better. Different times have been used for this. We generally use 7 days; some trials have used 14 days of not achieving a response to qualify as steroid refractory. The third definition is a bit more controversial. That involves patients who initially achieve a response and then, upon tapering of steroids, have a flare-up of their symptoms. That has been called steroid refractory in some trials. I tend to call that steroid dependent, and I think those patients have a less aggressive biology than the first 2 classes of patients who are regarded as truly steroid refractory.

The actual grade of the graft-versus-host disease at the time we declare people to be steroid refractory doesn’t factor into how I think about treatment very much. At that point, once a patient is steroid refractory, that’s their risk. I think about what the grade is at that point, though. I wouldn’t be surprised if, at the time of being steroid refractory, those with clinically more severe disease do worse than those with less severe disease. The important thing is that the graft-versus-host disease has shown itself to be steroid refractory, and you have to move on to another therapy.

In our routine practice, we go by the definitions I just said, so after adding high-dose steroids, we wait 3 days. If a patient gets worse, either with new organ involvement or worsening of their involved organs, then we move to therapy. In general, we wait at least 1 week to give treatments a chance to work.

Just as I talked about at the initial diagnosis, we do not have a good measurement in terms of biology of the disease. We’re very crude at judging if patients are responding. If I see a patient who’s being treated for acute graft-versus-host disease, I’m still looking at their skin rash, which is a good judgment. Is it fading? Is it getting darker? Less body surface involved? If the liver is involved, I’m looking at the level of bilirubin. If their GI [gastrointestinal] tract is involved, which are the majority of cases with steroid-refractory disease?

Unfortunately, we were looking at the volume of diarrhea in 24 hours. For many reasons, that is a crude and primitive way to judge response. Volume of diarrhea is influenced by many things: oral intake, use of narcotics, use of antibiotics. Even little swings in the volume of diarrhea that may or may not be accurately measured can dictate your judgment of response.

It emphasizes the point that you need to look at the whole patient to try to figure out if your treatment is working. Oftentimes, even though they might meet the definition of steroid refractory, you might wait because you think other signals are pointing to patients who are recovering.

For this patient, it was clear that at day 7, with things getting worse, she clearly met the definition of steroid refractory. In retrospect, we might have wanted to start with 2 mg/kg per day on day 1. Nobody knows if that would have made a difference, but there was already evidence of multiorgan involvement with all 3 organs, and especially the lower GI [gastrointestinal] tract, so that probably merited starting at 2 mg/kg per day instead of 1 mg/kg. We don’t know if that would have made a difference. It does emphasize our need to have better biomarkers for prognosis and response to help us ultimately be able to tailor our therapies appropriately.

Transcript edited for clarity.

Case: A 50-Year-Old Woman With Steroid-Refractory Acute Graft Versus Host Disease

Initial Presentation

• A 50-year-old woman presents on day +32 for a routine follow-up visit after myeloablative matched unrelated donor peripheral blood stem cell transplant for AML.She complains of a new erythematous macular rash and some mildly loose stools which she estimates is 450cc in 24 hours.
• PMH: unremarkable
• PE: rash noted on her neck, shoulders, and upper trunk (~60% BSA)
  
  

Clinical Work-up

• Labs: total bilirubin 2.7 mg/dl, AST 60 U/L, ALT 75 U/L
• Stool testing negative for bacterial/viral infection
• Negative for HBV, HBV, CMV, EBV, HHV-6
• Skin biopsy of the rash showed sparse inflammation and abundant dyskeratotic keratinocytes
• Flexible sigmoidoscopy showed patchy erosion and biopsy showed inflammatory cells with cryptitis
• She was diagnosed with aGvHD:
  • Skin stage 2
  • GI stage 1
  • Liver stage 1
  • Modified Glucksberg Criteria: grade II; MAGIC Criteria: grade II
• ECOG 1
  
  

Treatment

• Admitted as an inpatient for evaluation and initiated methylprednisolone 1.0 mg/kg and topical steroids
• No treatment response after 3 days, after dose increase of up to 2.0 mg/kg/day IV methylprednisolone
• After 7 days of systemic steroids diarrhea was around 1500 cc/day, rash was better
• She was started on ruxolitinib 5 mg PO BID which was tolerated well; increased to 10 mg PO BID 3 days later