In the treatment of leukemia, monitoring of residual disease is key to assessing treatment response and guiding clinical decisions. Oncogenic fusions are often disease defining, presenting a unique marker of leukemic cells that are not usually present in healthy cells. However, for KMT2A fusions – major oncogenic drivers of therapy-related acute myeloid leukemia – sensitive detection has been precluded by the wide spectrum of KMT2A fusion-partners.
Current testing options include bone marrow morphology (which offers limited sensitivity) and flow cytometry (which lacks convenience and standardization). Keen to offer an alternative, researchers from the Washington University School of Medicine in St. Louis have developed a droplet digital polymerase chain reaction (ddPCR) assay to detect the most common oncogenic KMT2A fusions (1).
“The aim of the study was to design and benchmark a pooled assay that would enable the simultaneous detection of multiple different fusions across the KMT2A locus,” explains corresponding author Grant A. Challen. “The assay detects these fusions by partitioning complementary DNA molecules into microfluidic droplets that are assayed with primers and probes that only produce a positive signal when fusion transcripts are present.”
According to the team, targeting these fusions broadly was previously difficult because of technical challenges and the rarity of some of these fusions. “This assay is easy to scale and validate, making it possible to expand it to cover additional fusions,” says Challen. “The assay is also inexpensive to run, enabling us to track disease trajectory more granularly during treatment, which may improve treatment decision-making in the future.”
In the study, the assay detected KMT2A fusions in patient samples known to harbor KMT2A fusions without producing false-positive signals in samples from healthy individuals.
Initially, the assay will be assessed for measurement of residual disease in clinical trials of targeted therapies for KMT2A-driven leukemia. “Long-term we plan to offer this assay diagnostically as a laboratory developed test for fusion-specific measurable residual disease detection,” concludes Challen. “This is a robust new tool for sensitive KMT2A fusion detection that is directly applicable for disease detection in patients with leukemia driven by these fusions.”
Newsletters
Receive the latest pathology news, personalities, education, and career development – weekly to your inbox.
References
- AL Young et al,. J Mol Diagn, 25, 12 (2023). PMID: 37813299.