Ultra-Sensitive DNA Test Identifies Relapse Risk in Aggressive Leukemia

Acute myeloid leukemia (AML) is a rare but aggressive blood cancer in which relapse after allogeneic stem cell transplant remains a major clinical challenge, particularly for patients with NPM1-mutated disease. Researchers now report that a highly sensitive next-generation DNA sequencing assay can identify minimal disease signals that predict post-transplant relapse risk. The work reflects a broader effort to tailor genetic testing to the specific mutation present in a patient’s leukemia.

Relapse after transplant persists despite advances in supportive care, and clinicians need reliable, mutation-informed methods to identify patients at greatest risk. Approximately 30% of adults with AML harbor an NPM1 mutation, and many proceed to allogeneic transplantation; however, standard approaches may miss very low-level disease. The ability to detect measurable residual disease (MRD) at extremely low abundance offers a potential path to more precise monitoring.

In the newest of four related studies featured in Bone Marrow Transplantation, a team led by researchers at Virginia Tech evaluated a next-generation DNA sequencing assay designed to detect minute traces of persistent NPM1 mutations in blood. By identifying MRD prior to transplantation, the test targets leukemia-associated mutations that fall below conventional detection limits. 

In the study, investigators analyzed blood samples from 190 adults with AML in clinical remission prior to allogeneic stem cell transplantation. The samples were obtained from a national biobank of transplant recipients treated between 2013 and 2019. The research was conducted as part of the Pre-MEASURE study within the Foundation for the National Institutes of Health (FNIH) AML MRD Biomarkers Consortium.

Results showed that patients with detectable mutated NPM1 prior to transplant were three to four times more likely to relapse and had significantly lower survival than MRD-negative patients. Even extremely low levels, estimated at fewer than one in 10,000 cells, were associated with worse outcomes, with relapse risk increasing as pre-transplant MRD levels rose. Among patients with the highest MRD burden, the three-year survival rate was 27%.

The Pre-MEASURE collaboration includes the National Marrow Donor Program’s Center for International Blood and Marrow Transplant Research (NMDP/CIBMTR) and investigators from Virginia Tech, Dana-Farber Cancer Institute of Harvard Medical School, and Fred Hutch Cancer Center, with participation from the U.S. Food and Drug Administration (FDA) and more than 20 pharmaceutical and medical diagnostics companies. A prospective follow-up study, MEASURE, is underway at 18 major U.S. cancer centers to validate and help implement the findings, with outcomes anticipated later this year.

“Large, carefully designed studies are essential for systematically improving the standards in how we monitor and treat this rare disease. Some genetic markers may appear promising, but without strong evidence they can be misleading. Precision medicine depends on building a solid foundation so these powerful technologies can be used responsibly,” said Christopher Hourigan, professor at the Fralin Biomedical Research Institute and director of its Cancer Research Center in Washington, D.C.

Related Links
Fralin Biomedical Research Institute
Virginia Tech Carilion School of Medicine