Transplant-Associated GvHD - Episode 1

Case 1: Steroid-Refractory Acute GVHD

The experts discuss a case presentation of a 50-year-old woman with acute GVHD, risk factors for GVHD, and initial treatment options.

Yi-Bin Chen, MD: Thank you for joining us for this Targeted OncologyVirtual Tumor Board®, which is focused on graft vs host disease [GVHD]. In today’s presentation, my colleagues and I will review 2 clinical cases. We will discuss treatment approaches for each patient and review key clinical trial data that have affected our clinical practice. I am Dr Yi-Bin Chen from Massachusetts General Hospital in Boston, Massachusetts. I’m joined by Dr Pashna Munshi from MedStar Georgetown University Hospital in Washington DC, and Dr Nelson Chao from Duke University in Durham, North Carolina.

Pashna N. Munshi, MD: This is a 50-year-old woman who complains of changes to her skin and new diarrhea that developed over the last few days. She’s 30 days following a myeloablative allogenic transplant for the treatment of AML [acute myeloid leukemia]. On a physical exam, she has an erythematous maculopapular rash that covers about 60% of her body, approximately 500 mL of watery diarrhea per day, and her performance status has an ECOG of 1. Including her blood work, she has a bit of anemia. She has hemoglobin of 10.2 g/dL. In terms of her electrolytes, they seem OK, but when you look at her bilirubin, she has a bit of jaundice; her total bilirubin has increased to 2.5 mg/dL with a mild transaminitis with ALT [alanine transaminase] of 93 U/L and AST [aspartate aminotransferase] of 88 U/L.

She was admitted to the hospital for evaluation and a work-up. She underwent some blood tests, which were negative for hepatitis viruses, hepatitis B and C virus, cytomegalovirus, Epstein-Barr virus, and HHV-6 [human herpesvirus 6]. She underwent stool testing because she had diarrhea, and that was negative for bacterial or viral infection. Because of the rash, she had a skin biopsy, and that showed abundant dyskeratotic keratinocytes. Because of the diarrhea, she also had a colonoscopy, which showed patchy erosive changes. A biopsy revealed inflammatory cells with multiple apoptotic cells and several lymphocytes. She was diagnosed with acute graft vs host disease, overall criteria based on MAGIC, which is the Mount Sinai Acute GVHD International Consortium. She was graded as 2 because of skin stage III, GI [gastrointestinal] stage I, and liver stage I.

Yi-Bin Chen, MD: This seems like a fairly straightforward case of acute graft vs host disease that involves the skin, the liver, and the lower GI tract, meeting an overall grade 2. Acute graft vs host disease is graded on a scale of 1 through 4 in overall disease. Generally, we think grades 2 through 4 are clinically significant. They require systemic treatment and affect the overall outcome. The first question to my colleagues is, how often do we see this? What’s the incidence of grades 2 through 4 acute graft vs host disease after transplant at your center?

Nelson Chao, MD: It varies depending on the type of donor and transplants. Whether it’s ablative or nonablative, whether it’s a haploidentical or cord blood, but in the aggregate, about 50% will have grade 2 to 4. Over the years, it’s been consistent.

Yi-Bin Chen, MD: Dr Munshi, how about your center?

Pashna N. Munshi, MD: I agree. It depends on the regimen used. These days a lot of us are using post-transplant cyclophosphamide. I use that as well as prophylaxis for GVHD. Maybe we see less acute GVHD, but that has yet to be seen. It has not been compared with others at our site. It’s in that range of 50% overall.

Yi-Bin Chen, MD: I agree with that as well. Our results would be comparable. Some centers may have more, or some may be less based on how aggressive we are at diagnosing upper GI GVHD. That seems to move the needle back and forth. Overall, we see about 40% to 50%. Dr Chao, you mentioned some of the risk factors for acute graft vs host disease that we think about: type of donor and regimen. Are there other risk factors that predispose patients to acute GVHD?

Nelson Chao, MD: There are a handful. The amount of disparity, the donor gender, the intensity of the prep regimen, the type of GVHD prophylaxis that’s used, peripheral blood vs bone marrow, where peripheral blood is higher, and CMV [cytomegalovirus] status is important. Those are the major things that come to mind.

Yi-Bin Chen, MD: Would it be fair to say that while we keep these risk factors in mind, none of them truly alters how we might manage a patient practically? We all have different regimens for prevention, depending on the type of donor and HLA [human leukocyte antigen] disparity, but other factors we keep in mind and know for a patient. We wouldn’t treat a myeloablative patient different from a reduced-intensity patient.

Nelson Chao, MD: That’s true. The only potential difference is the additional ATG [anti-thymocyte globulin] that people use sometimes and that they match unrelated donors. This is institution dependent.

Yi-Bin Chen, MD: With what this patient presents, she has been hospitalized and undergoes initial evaluation. She has a diagnosis of new acute graft vs host disease. Is there anything that then happens at your center? Is there an infrastructure to treat these patients or to put them on clinical trials? Can you describe what bells go off when there’s patient is diagnosed with acute graft vs host disease?

Pashna N. Munshi, MD: If there’s a presence of a clinical trial, certainly if the patient is eligible and you can get them on a trial for acute GVHD quickly, yes. But once you’ve ruled out infection like this case has, we want to start treatment quickly. The first step in somebody with significant acute GVHD is the initiation of systemic steroids. That’s how I would approach this case. That’s what we do at our center, involving all the other supportive teams, the GI groups, or nutrition that’s needed for patients who have GI loss. It’s needed.

Yi-Bin Chen, MD: Certainly, as we’ve had more clinical trial options available for these patients, we tend to alert the entire team when we think a patient has acute graft vs host disease. We’re able to offer these opportunities to patients. Dr Chao, you’ve done this the longest among the panelists here. What would the treatment options be for this patient, and have they changed over the last couple of decades for this newly diagnosed acute graft vs host disease?

Nelson Chao, MD: They haven’t changed much. Steroids have been the foundational therapy. Data and trials have been done. Sirolimus up front, instead of steroids, for example. Steroids work about 50% to 60% of the time, so that’s good. There are many problems with steroids; there are adverse effects. Being able to get them off quickly or use something that spares steroids would be very useful.

Yi-Bin Chen, MD: Do you think there’s any role to add something in addition to steroids, or should that be done purely on a clinical trial at the moment?

Nelson Chao, MD: I would say only on a clinical trial.

Yi-Bin Chen, MD: Dr Munshi, you had mentioned that for this patient you’d start steroids pretty quickly and not delay. What’s making you say that? Why do you feel we need to initiate treatment right away?

Pashna N. Munshi, MD: We’re going to review some of the REACH2 data but also look at data from the REACH-1 study and looking at steroid-refractory acute GVHD, these are patients who can progress quickly to involvement of other organs if they’re not treated rapidly. We know that the mortality in these patients with severe GVHD can be as high as 80%, more than 50% for sure if it’s not controlled. As Dr Chao said, 50% to 60% of these patients may not respond to steroids initially. Before the horse is out of the barn, so to speak, once an acute GVHD has happened, we need to stomp down the fire.

Yi-Bin Chen, MD: We all agree. Even though she meets MAGIC overall grade 2 disease, what’s worrying us the most is the evidence of multiorgan involvement, including the liver and the lower GI tract, specifically the lower GI tract. We’d want to jump on this right away to prevent it from getting worse. If it was just skin stage III, there could be some liberties taken if we’re waiting for a clinical trial or other tests. However, the evidence of actual visceral involvement makes us nervous for this patient.

This transcript has been edited for clarity.