Protective predictions

NEW YORK—Graft-versus-host disease is a leading issue when it comes to bone marrow transplants, one that affects nearly half of all recipients. It is the result of a bone marrow donor's immune system perceiving the recipient’s body as foreign and launching an immune response, which manifests as attacks on the recipient's tissue—primarily the skin, liver and gastrointestinal tract. It is estimated that between 40 and 60 percent of patients who receive bone marrow transplants develop severe graft-versus-host disease, and approximately 40 percent of people who develop the disease die. Given that the individuals that receive bone marrow transplants are generally already severely ill—this treatment is often used in cases of leukemia, lymphomas and multiple myeloma—the addition of graft-versus-host disease is a further strain on the immune system that patients can hardly afford.

There are no tests currently that can predict graft-versus-host disease before the symptoms manifest, but that could change soon thanks to a team at the Mount Sinai Acute GVHD International Consortium (MAGIC), which has developed an algorithm to predict a patient's risk of developing graft-versus-host disease. The work was published in the Journal of Clinical Investigation Insight, in a study titled “An early-biomarker algorithm predicts lethal graft-versus-host disease and survival.”

As noted in the study, “Pretransplant clinical risk factors for GVHD include the degree of human leukocyte antigen (HLA) match between donor and recipient, recipient age, donor type and conditioning regimen intensity. Some centers use one or more of these risk factors to guide GVHD prophylaxis, such as the use of anti-thymocyte globulin when the donor is not an HLA-identical sibling, but such approaches are globally immunosuppressive and carry their own risks, in particular of opportunistic infections.”

The study was an international undertaking at 11 cancer centers and focused on blood samples from nearly 1,300 bone marrow transplant patients. The team measured the concentrations of four biomarkers for graft-versus-host disease—ST2, REG3a, TNFR1 and IL-Ra—in blood samples taken one week after hematopoietic cellular transplantation and “used them to model six-month NRM [nonrelapse mortality] using rigorous cross-validation strategies to identify the best algorithm that defined two distinct risk groups,” as noted in the study. They settled on what they called the MAGIC algorithm, which measures concentrations of ST2 and REG3a, and found that it “identified patients with a cumulative incidence of six-month NRM of 28 percent in the high-risk group and 7 percent in the low-risk group.”

“The MAGIC algorithm gives doctors a roadmap to save many lives in the future. This simple blood test can determine which bone marrow transplant patients are at high risk for a lethal complication before it occurs,” explained Dr. James L.M. Ferrara, Professor of Pediatrics, Oncological Sciences and Medicine, Hematology and Medical Oncology at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and co-director of MAGIC. “It will allow early intervention and potentially save many lives.”

Mount Sinai's doctors are now at work arranging clinical trials to explore whether or not immunotherapy drugs used during the onset of graft-versus-host disease could benefit patients if administered as soon as the MAGIC blood test highlights them as being at risk for a severe onset of the disease. It's thought that if such drugs are administered before symptoms develop, it could mitigate the force of the disease reaction and prevent fatalities.

“This test will make bone marrow transplant safer and more effective for patients because it will guide adjustment of medications to protect against graft-versus-host disease,” Dr. John Levine, Professor of Pediatrics and Medicine, Hematology and Medical Oncology at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai and co-director of MAGIC, said in a press release. “If successful, the early use of the drugs would become a standard of care for bone marrow transplant patients.”