A 53-Year-Old Man With Steroid-Refractory Acute Graft-Versus-Host Disease - Episode 7

Managing Acute GVHD in Community Settings

Newer therapies being explored to address treatment gaps in acute graft-versus-host disease (GVHD), and advice to community oncologists/hematologists who manage cases of GVHD and/or care for patients who receive allotransplants.

Michael Bishop, MD: There are still massive unmet needs for patients with steroid-refractory acute graft-versus-host disease [GVHD]. Acute GVHD is still a major cause of morbidity and mortality, even though we’ve got ruxolitinib. Again, 50% of patients are either going to be steroid refractory or steroid dependent. Among those patients, the outcomes are abysmal, with a 50% mortality rate. We also see morbidity in patients who respond to corticosteroid administration. I have seen a lot of problems related to that. Thinking about ruxolitinib, what about the 25% to 30% of patients with grade 2 disease who don’t respond? What about the other 50% to 60% with grade 3 or grade 4 disease? And then what about the toxicities? Those are our challenges, and we have to get to the point where we can care for patients better.

Where do we go moving forward? There are a number of newer therapies that people are looking at to be complementary. I think when we look at ruxolitinib, we look at pathways. One is the JAK pathway. Well, there are other pathways that are involved in either tissue inflammation or T-cell activity and function. And so, I’m most excited about small molecules, which have relatively low toxicity profiles and target the pathways that we know are involved in graft-versus-host disease. There are still people going back to the same treatments I saw being used when I first starting doing allogeneic stem cell transplantation. A lot of the things have not changed in 30 years. Now people are saying, “Well, maybe we can add these newer things to the old things.” That may be correct.

Ruxolitinib is the only drug approved for steroid-refractory acute graft-versus-host disease, yet we’ve been dealing with this for nearly 50 years, and this is the first drug approved. We have a long way to go. But now that we’re homing in on the biology, I think targeting those pathways will be important. Those are the things I’m most excited about. I think that’s the future for the treatment of acute graft-versus-host disease.

I think Bruton tyrosine kinase is another pathway that is very exciting, and it is different from the JAK pathway. Some of the monoclonal antibodies are targeting specific proteins expressed on the surface of T cells that may inhibit their trafficking. People are also looking at targeting hedgehog [signaling pathway], which also plays an important role in T-cell activation. Again, this is all because we now have a deeper understanding of the biology of the disease. Those are the trials that I’m most interested in hearing about and seeing, because they’re taking on acute graft-versus-host disease from perspectives that we haven’t tested before.

I think if I had one piece of advice for community oncologists, we’re markedly better at treating patients with allogeneic stem cell transplantation. I mentioned we’ve been doing this for close to 50 years. But if you look at the last 3 decades, treatment-related mortality rates have dropped in every single decade. That’s because we have better supportive care measures. The other thing that is important to know is that there’s not an age limit. As a matter of fact, almost any patient at any age can successfully go through allogeneic stem cell transplantation. It’s more physiologic age than chronologic age.

If you look at the SEER [Surveillance, Epidemiology, and End Results program] data, older patients who go through an allogeneic transplant do better in terms of survival than patients who don’t go through a transplant. The greatest fear is, “Oh, I don’t want my patient to get graft-versus-host disease.” This is because the only time oncologists ever see transplant patients is when they are in the hospital. Guess who gets admitted to the hospital? The sick patients do. They never see those patients who are long-term survivors, who are doing great outside the hospital. But now with a better understanding of the biology, we’re able to treat better, and we’re having a significant impact on how patients are doing, particularly in regard to their quality of life. Those are the things I would want community oncologists to know about allogeneic stem cell transplantation, in general, and acute graft-versus-host disease, specifically.

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