Earlier this year, ctDNA testing joined the National Comprehensive Cancer Network (NCCN) guidelines for monitoring of PET-positive diffuse large B-cell lymphoma (DLBCL). This movement offers a biopsy alternative and provides a significant advancement in lymphoma care.
One such ctDNA measurable residual disease (MRD) assay was validated for use at the end of DLBCL treatment in a real-world study presented at ASCO 2025. Here, we speak with study co-author, David Kurtz, Chief Medical Officer at Foresight Diagnostics, about the use of ctDNA-MRD assays and the opportunities they present for diagnostics.
What are the advantages of ctDNA-MRD assays over other minimal residual disease (MRD) detection methods?
Traditional methods for detecting MRD, like flow cytometry or PCR, work for some blood cancers but have limitations. They often lack sensitivity and aren’t suitable for all lymphoma types – especially those without cancer cells in the bloodstream, like DLBCL.
Testing for ctDNA-MRD helps overcome these issues. Newer tests, such as Foresight CLARITY™, are highly sensitive and can detect tiny traces of ctDNA from a simple blood sample. In fact, its detection limit is less than 1 part per million. Unlike earlier ctDNA-MRD tests, which sometimes missed cancer when tumor levels were low, advanced assays like this are much more accurate after treatment.
Can you explain the significance of ctDNA-MRD testing being included in the NCCN guidelines for DLBCL?
This is a big step forward in the field – showing growing support for using ctDNA-MRD testing as part of routine care. The guidelines still recommend PET/CT scans at the end of treatment to check response, but they also note that PET scans can give false-positive results. In those cases, follow-up testing – usually a biopsy or another PET scan – is suggested. Now, ctDNA-MRD offers a reliable, noninvasive alternative to confirm PET-positive results. Its inclusion in the NCCN guidelines highlights its proven value and could help make it a standard part of managing DLBCL.
Why was end-of-treatment (EOT) ctDNA testing chosen as the focus for this study?
The EOT is a key point for assessing response in DLBCL. It’s also when doctors decide whether a patient needs more treatment for remaining disease or can move into regular monitoring. That makes it the perfect time to use MRD testing as an objective way to detect any leftover cancer.
Previous studies had already shown that the Foresight CLARITY™ MRD test works well at this stage, but most of that data was from past cases. What was missing was a real-world, forward-looking study to confirm its value. This new study aimed to fill that gap – to prove how well EOT ctDNA-MRD works and build confidence as MRD testing becomes more widely used in guidelines and everyday care.
What were the main outcomes of your study?
The results were compelling. The study showed that using the Foresight CLARITY™ ctDNA-MRD test at the EOT gave strong predictions about patient outcomes in DLBCL. The test had over 80 percent sensitivity for detecting patients who would relapse within a year. MRD status was closely linked to both progression-free and overall survival – patients who tested MRD-positive were much more likely to experience a recurrence.
One of the most important findings came from cases where PET scan and MRD results didn’t match. Among patients with a negative PET scan, those who still had detectable MRD had a much lower 3-year progression-free survival (36 percent) compared to those who were negative on both tests (89 percent). On the flip side, PET-positive patients who were MRD-negative had a 64 percent 3-year survival rate – far better than the 4 percent seen in patients who were positive on both tests. These results show that ctDNA-MRD can be a more reliable indicator of relapse risk than imaging alone, especially when PET results are unclear or misleading.
How should pathologists interpret MRD results in cases where imaging shows complete response?
When a PET scan shows no signs of disease after treatment, but ctDNA-MRD is still detectable, it likely means there’s still some lymphoma left. Our data consistently show that these patients have a high risk of relapse. MRD testing provides a deeper, molecular look that can catch disease PET scans might miss. In such cases, doctors might consider enrolling patients in clinical trials like ALPHA3, which are testing whether continued treatment – like using CAR T-cell therapy – can reduce or prevent the chance of relapse.
How should diagnostic teams handle discordance between ctDNA-MRD and PET results?
The NCCN guidelines offer clear direction. If a PET scan is positive after treatment but a biopsy can’t be done, highly sensitive ctDNA-MRD testing can help clarify the result. If MRD is positive, the patient likely still has disease and may need second-line treatment. But if MRD is negative, the guidelines suggest moving to surveillance instead of continuing therapy. This is based on data showing that MRD-negative patients often do well without more treatment – avoiding unnecessary costs, side effects, and interventions.
How does the sensitivity of MRD assays impact tissue and liquid biopsy interpretation, particularly in borderline or minimal disease settings?
In cases where very little disease remains, test sensitivity is crucial. If ctDNA levels are extremely low, less sensitive tests may miss it, leading to false negatives and giving patients and doctors a false sense of security. Highly sensitive tests like Foresight CLARITY™, which can detect ctDNA at parts-per-million levels, reduce this risk by reliably spotting even tiny amounts of disease. This leads to better, more informed decisions.
How should pathology labs prepare for the expected increase in demand for MRD testing in DLBCL and possibly other hematologic malignancies?
Our assay is tumor-informed, which means it uses a patient’s pre-treatment sample to find specific genetic changes in their tumor. These changes are then tracked over time to detect MRD. Because of this, it's important for pathology labs to preserve enough tissue – not just for diagnosis, but also for future MRD testing.
Labs should avoid using up tissue on unnecessary tests and focus on what’s clinically important. They should also have clear processes for sending FFPE blocks or slides to specialized labs when needed. As MRD testing becomes more common, good coordination between pathology, oncology, and testing labs will be essential for timely and effective use in patient care.
Do you foresee ctDNA-MRD assessment becoming a routine diagnostic marker beyond DLBCL?
Absolutely. We’re already seeing encouraging results in other cancer types. In classical Hodgkin lymphoma, ctDNA-MRD detection could help reduce the need for aggressive treatment. In slower-growing lymphomas, it may support gentler monitoring approaches. For solid tumors, there’s growing interest in using MRD after treatment to guide decisions about additional therapy – especially for high-risk patients, where catching residual disease early could improve outcomes.
However, we still need more data. Including ultra-sensitive ctDNA-MRD testing in clinical trials – where results are used to guide treatment – will help build the evidence needed to get MRD into official guidelines for more cancers.
What are the next steps for this research?
The purpose of MRD testing isn’t just to detect relapse earlier. Finding molecular signs of relapse is only helpful if it leads to clear clinical action – otherwise, it may cause unnecessary worry for patients. Our goal is to create and validate ctDNA-MRD tests that support real treatment decisions and can be used in everyday care.
We’re building on the results of our recent study by testing how ctDNA-MRD can guide treatment. One key example is the ALPHA3 trial, where patients who are MRD-positive but PET-negative may receive CAR T-cell therapy. Foresight CLARITY™ is being used in this study under special approval. The aim is to show that MRD testing at the end of initial treatment can help identify patients who might benefit from continued therapy.
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