A pair of biomarkers are being used to guide treatment and predict mortality in patients with graft-versus-host disease (GVHD), according to James L.M. Ferrara, MD, DSc, of the Icahn School of Medicine at Mount Sinai, New York. In this episode, Dr. Ferrara explains how measuring these biomarkers – REG3-alpha and ST2 – can prevent over- and undertreatment of acute GVHD. The biomarkers have also been shown to predict nonrelapse mortality more accurately than a change in clinical symptoms. Before reviewing these findings, Dr. Ferrara tells host David H. Henry, MD, what GVHD is, how to recognize it, and how it’s typically treated. GVL and GVHD GVHD is “very tightly associated” with the graft-versus-leukemia (GVL) effect, Dr. Ferrara explained. The GVL effect refers to the ability of donor immune cells to eliminate host malignant cells after allogeneic hematopoietic stem cell transplant (allo-HSCT). The donor T cells respond to minor histocompatibility antigens on malignant cells but also on normal cells. When the donor T cells attack the normal cells, the patient develops GVHD. To prevent GVHD, patients may receive cyclosporin, tacrolimus, methotrexate, sirolimus, or other drugs in various combinations. Despite prophylaxis, slightly under half of allo-HSCT recipients will still develop some form of GVHD, Dr. Ferrara said. Acute GVHD Acute GVHD typically occurs in the first month or two after transplant, and about 50% of cases happen in the first month, Dr. Ferrara said. There are three primary targets – the skin, liver, and GI tract. The rash observed with skin GVHD is vesiculopapular, and the extent of the rash determines the stage of GVHD in the skin. Increase in total bilirubin is used to measure the stages of liver disease. GVHD in the GI tract is characterized by persistent nausea and vomiting or diarrhea (up to liters a day). Evaluating the skin, liver, and GI tract together can provide the overall GVHD grade, between 1 and 4. Grade 4 GVHD is the most severe, and grade 1 is a skin rash that usually affects less than 50% of the body surface area. Over- and undertreatment When GVHD is mild and limited to the skin, topical steroid creams are adequate treatment. When GVHD progresses into the GI tract and liver, patients require systemic immunosuppression. However, it’s difficult to tell whether GVHD is going to be mild, moderate, or severe. So when patients with acute GVHD receive systemic steroids at a starting dose of 1 mg/kg, many of these patients are overtreated “and a fair number of them are undertreated because we don't actually know which patients are going to progress and which patients are going to respond to treatment,” Dr. Ferrara said. He noted that the JAK1/2 inhibitor ruxolitinib was approved to treat steroid-refractory acute GVHD last year. Prior to that, the only approved treatment for GVHD was systemic steroids. Biomarkers signal disease severity Through their research, Dr. Ferrara and colleagues identified two biomarkers of GVHD severity – REG3-alpha and ST2. “When the GI tract is damaged early, these proteins flood into the systemic circulation, and they can actually tell us who's got a damaged GI tract very early, even before one has symptoms like diarrhea,” Dr. Ferrara explained. The biomarkers can be used to assess, at the onset of GVHD, whether or not a patient has crypt damage and needs more intensive treatment. Biomarkers guide treatment, predict outcomes Dr. Ferrara and colleagues used serum samples collected by the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop MAGIC Algorithm Probability (MAP). MAP is calculated from patients’ levels of REG3-alpha and ST2 and can be used to predict the risk of severe GVHD. “You put these two biomarkers into an equation, you get a single number, and that number tells you whether [the patient is] high risk, low risk, or intermediate risk,” Dr. Ferrara explained. He and his colleagues found they could use MAP to predict patients’ response t