Unmet Needs in the Management of 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

EP: 4.Defining Steroid Refractory aGvHD

EP: 5.Treatment Options for Steroid Refractory aGvHD

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EP: 6.Unmet Needs in the Management of aGvHD

Yi-Bin Chen, MD: Looking forward, a lot of room remains for improvement and research in acute graft-versus-host disease [aGvHD]. When we talked about the case that I presented, what I mentioned was the initial assessment of the biology for the patient since the origin of acute graft-versus-host disease is really an adaptive immunological response, which we think takes weeks to develop.

I would think we would be able to develop assays or tests that give us a glimpse into this immune response before actual clinical symptoms. There has been some work done along these lines; the MAGIC [Mount Sinai Acute GVHD International Consortium] biomarkers we mentioned have not shown themselves to be necessarily predictive but can stratify into risk groups, from biomarkers taking a week after transplant to those who will ultimately develop graft-versus-host disease. More sensitive and specific tests would help us intervene in a preemptive fashion before having patients experience the morbidity of clinical graft-versus-host disease.

At diagnosis, we will hopefully be able to develop risk-stratified treatments, so patients who we truly believe are high risk can be treated differently. There are patients who should receive steroids plus another drug up front to help bring about a response. Then, there are patients who are ultimately low risk. These patients may not need steroids at all and can be treated with an alternative, less toxic agent, or perhaps they’re initially treated with steroids and achieve a response. Then, we’re able to decrease the steroid much faster than we already do. This gets into the judgment of response, which is primitive. It’s still based on clinical observation of the body surface area, skin rash, the measurement of the total bilirubin value, and the assessment of the volume of diarrhea in 24 hours.

When patients are in the hospital, we round on them every 24 hours. We’re impatient and want to see improvement on a daily basis. As I mentioned, though, the time it takes for the gastrointestinal epithelium to heal after such severe injury does not mesh with our inpatient time scale. Our estimation of response based on these metrics is wholly inaccurate, so we need to develop better ways to monitor patients, judge if they’re getting better, and gauge whether improvements are working or if they are getting worse and need to add something else.

Hopefully, research can be done to better our clinical judgment, which could lead to a better assessment on clinical trials or if treatments are working. Clinical trials are difficult. There’s no doubt about that for this patient population. It’s a rare disease that has a heterogeneous biology. This is why many clinical trials in the past have ultimately failed or did not accrue and were closed early.

You can see why the judgment of response plays a huge role in these clinical trials. If you start drug X and decide to move to another therapy if the diarrhea volume is not getting better by day 4, then you’ve ultimately declared that patient to be a failure of drug X or drug X to be a failure for that patient. If you had just waited 3 more days, the diarrhea may have gotten better because the kinetics of how the GI [gastrointestinal] epithelium heals is different from what you want it to be. You can see how clinical trials are ultimately dependent on how we behave and judge a response. That’s an obstacle at large in the community that we’re trying to fix.

Lastly, we need different agents. Graft-versus-host disease used to be thought of as just a Th1-driven T-cell response. As it becomes steroid refractory, it involves different pathways of inflammation, immunology, etc, to the point that it is no longer a T-cell–driven process.

The traditional approach of hammering away at the immune system did not lead to success. It only led to incidence of opportunistic infections and death. The newer treatments do target different pathways. Ruxolitinib is an example that targets the JAK1 and JAK2 pathways that signal for a lot of proinflammatory cytokines. That is at the heart of why we think it has some effect, but I’m sure there are other pathways that are involved for patients who have steroid-refractory acute graft-versus-host disease that need to be explored.

Lymphocyte trafficking is another avenue that both myself and others have looked into. Fixing the microbiome is yet another modality that we can address through probiotics or fecal transplantation. Looking at these other pathways of inflammation will be pivotal to our understanding. There are a lot of people with steroid-refractory aGvHD that probably have some evidence of localized TMA [thrombotic microangiopathy], and we see that in biopsies if we look hard enough. Perhaps targeting the endothelium as a target of graft-versus-host disease in this specific organ can help patients, as well.

These are just a few of the avenues that we’re doing research in to hopefully improve outcomes for this unfortunate group of patients.

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