Acute Graft-Versus-Host Disease: Diagnostic Criteria & Prevention

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

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

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: Acute graft-versus-host disease is defined both clinically and pathologically. We primarily define graft-versus-host disease by involvement of 3 organs. First is the skin, which is clinically defined by rash. The second organ is gastrointestinal [GI]. For GI, however, we have to think about whether it’s upper or lower GI involvement. Upper GI involvement may present with difficulty swallowing, nausea and vomiting, lack of appetite. We define lower GI involvement as onset, frequency, and volume of diarrhea in its most severe form—abdominal cramping and bleeding from the intestinal tract. Then in regard to the third organ involvement, we define this as a rise in bilirubin, which is generally accompanied by a subsequent rise in liver transaminases, AST [aspartate aminotransferase] and ALT [alanine transaminase]. When you see an isolated rise in bilirubin without a rise in transaminases, you have to be looking for other causes. But taking all 3 of those together is how we define the disease clinically.

We also try to define acute graft-versus-host disease pathologically. We heard in this case presentation that the patient had a skin biopsy and colon biopsy. It’s important to realize that with graft-versus-host disease of the intestinal tract, 70% to 90% of the time a flexible sigmoidoscopy is sufficient for a patient with diarrhea. You don’t have to do an entire colonoscopy. So we define acute graft-versus-host disease clinically and confirm it pathologically.

The frequency of acute graft-versus-host disease is highly dependent upon a number of factors. When we talk about how common it is, as a general statement, in patients undergoing allogeneic stem cell transplantation, the incidence can be about 25% to 50%. This incidence rate demonstrates patients who are deemed to have clinically significant graft-versus-host disease. Clinically significant means they develop involvement where you see the clinical manifestations in the skin, the gut, and the liver. But it depends on what you’re using for graft-versus-host disease prophylaxis. If you’re doing an in vivo or ex vivo T-cell depletion, the incidence of graft-versus-host disease is going to be lower than when you do a T-cell–replete, for which you leave the T cells in the graft, or you don’t try to significantly remove them afterward using monoclonal antibodies targeting T cells. So, there’s going to be that difference.

There’s also going to be a difference based upon risk factors. Risk factors for development of acute graft-versus-host disease depend upon the type of graft you’re using—whether it’s from an HLA [human leukocyte antigen]-matched sibling versus an HLA-matched unrelated donor, or if you’re using a partially matched donor. HLA matching plays a significant role. Other factors include both the recipient age and the donor age. Another factor is whether either the recipient or the donor is serology-positive for CMV [cytomegalovirus]. Another important factor is whether the donor is male or female. The incidence of acute graft-versus-host disease is much higher when associated with a female donor. The reason is females, because of going through pregnancy, are exposed to minor histocompatibility antigens. Therefore, the immune cells that are passively transferred in the stem cell graft are more primed against these minor histocompatibility antigens that are known to be associated with the development of acute graft-versus-host disease. Those are some of the most important risk factors for developing acute graft-versus-host disease.

There’s a wide variety of regimens that are used to prevent acute graft-versus-host disease. The most common regimen that is used internationally is a combination of a calcineurin inhibitor, such as tacrolimus or cyclosporine, with methotrexate. The methotrexate is usually given on days 1, 3, 6, and 11 following the stem cell infusion. Another more frequently used method to prevent graft-versus-host disease is post-transplantation cyclophosphamide. This was developed by the Johns Hopkins University group and has been demonstrated to permit the use of haploidentical stem cell grafts. It is now being used in the matched volunteer setting, and also in some situations, the matched sibling setting.

The other major way to prevent graft-versus-host disease is through T-cell depletion, and that can be ex vivo, where the graft, before it’s infused, goes through a process, usually through a selection column to remove T cells from the graft. T-cell depleted grafts have a much lower incidence of graft-versus-host disease. There are also forms of in vivo T-cell depletion using monoclonal antibodies such as antithymocyte globulin or alemtuzumab. Those are the most common regimens used to prevent graft-versus-host disease.

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