Chronic graft-versus-host-disease (GVHD) is a fibro-inflammatory process that affects multiple body systems and can lead to organ damage and in some cases, death. It continues to be the most common cause of late nonrelapse mortality – which is why this is a concern for patients undergoing allogeneic stem cell transplants. Experts at 65th American Society of Hematology (ASH) Annual Meeting discussed ways to treat, prevent, and predict who will get it at a session, entitled “Graft Versus Host Disease: Is an Ounce of Prevention Worth a Pound of Cure?” Here are the main points.
Why is GVHD So Problematic?
The number of GVHD cases is increasing due to many factors, including demographic changes in patients who are undergoing allogeneic transplant and the increasing use of peripheral blood stem-cell grafts, said Idoroenyi Amanam, MD, with City of Hope in Duarte, California.
Changing demographic factors include more older patients receiving transplants and more female-to-male transplants.
While allogeneic stem-cell transplant can cure malignant and nonmalignant hematologic disorders, “chronic GVHD is a significant hurdle for long-term survival,” he said.
About 15% of post-allogeneic transplant deaths after day 100 are related to GVHD, he said, adding that the decreased quality of life and financial burden is substantial. About 40% of patients who develop GVHD develop severe disease and have four or more organs involved, he said.
How Can GVHD Be Prevented?
Methotrexate is still the most widely used prevention therapy, Dr. Amanam said. For adults, that’s methotrexate without antilymphocyte globulin (ATG) and for children under 18, it’s methotrexate with ATG, according to the Center for Blood and Marrow Transplant Research.
Calcineurin inhibitors with four doses of methotrexate has been the standard of care for a long time but the options are slowly evolving, he said.
Dr. Amanam pointed to a combination showing promising results in a phase 3 study reported in the New England Journal of Medicine this year. Adults were randomly assigned to receive cyclophosphamide–tacrolimus–mycophenolate mofetil (an experimental prophylaxis) or tacrolimus–methotrexate (the standard prophylaxis). They found that relapse-free survival at one year was significantly more common among those who received the experimental combination than those who received the standard strategy.
Can Biomarkers Help Predict Who Will Get GVHD?
Kirk Schultz, MD, professor of pediatrics with the University of British Columbia in Canada, talked about the need for better biomarkers or clues within the body to help identify whether someone is at risk for developing chronic GVHD or acute GVHD.
The biomarkers to predict acute GVHD need to be performed as close to time of transplant as possible up to 14 days, he said, so assignment to therapy can happen quickly.
With chronic GVHD, “we have a little more time,” but he said that most biomarkers currently in use have been done at 100 days. “That’s actually not optimal,” he said, “because about 10% of the cases of chronic GVHD will occur before 100 days.”
He said the best time to use biomarkers is from 42 days after transplant to 60 days.
What Are the Challenges of Using Biomarkers to Predict GVHD?
One of the reasons it’s been hard to develop good biomarkers for predicting chronic GVHD is because the GVHD definition is evolving.
Atypical chronic GVHD is now becoming better recognized, Dr. Schultz said. He pointed to a recent National Institutes of Health (NIH) paper that outlines many atypical manifestations of chronic GVHD that are not currently well-identified in the NIH critical criteria.
Examples of the manifestations include atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes (the thin membranes that line organs such as the heart and lungs and body cavities).
These atypical features may contribute significantly to patient morbidity and to deaths, the paper said, but have not been well-studied.
Dr. Schultz said he and colleagues are studying whether there is more than one kind of GVHD with the help of artificial intelligence machine learning. “When we have biomarkers or an intervention, we have to think about that,” he said.