How Are We Detecting Residual Disease in Lymphoma Today?

This podcast explores the principles and clinical applications of circulating ctDNA-based MRD testing in diffuse large B-cell lymphoma, including how personalized sequencing assays can detect microscopic residual disease with greater sensitivity than imaging. Dr David Russler-Germain discusses the growing evidence supporting ctDNA MRD testing for prognostication and treatment monitoring, while also addressing current limitations, such as variability across lymphoma subtypes and factors that can affect assay performance and interpretation.

Kelly Conger: Hello, and welcome to the Oncology Learning Network. I'm Kelly Conger, and on today's podcast, we will be discussing methods of residual disease detection in lymphoma. I am joined by Dr David Russler-Germain. Welcome, Dr Russler-Germain. We are excited to have you here with us today to share your expertise in lymphoma residual disease detection. To start us off, can you describe the classic end-of-treatment protocol for lymphoma patients and why detection of residual disease is so important in this patient population?  

Dr Russler-Germain: Using diffuse large B-cell lymphoma or DLBCL as the predominant and most common aggressive lymphoma that we treat with curative intent, we use tools such as PET scans to assess patients' end-of-treatment response in order to actually estimate whether they're likely to be cured or not. The goal of frontline treatment is to eradicate the disease, have patients achieve a complete metabolic response by PET scan, and move on to a surveillance period where they're off therapy, and hopefully in years we can call that remission a cure. Unfortunately, roughly 40% of patients with DLBCL relapse after frontline therapy — and albeit PET scans are better than CAT scans — we are still unable to optimally identify which patients are at the highest risk of recurrence. 

Kelly Conger: You mentioned PET-CT scans as a way to determine metabolic response to treatment. Can you tell us a little more about how PET-CT scans work and how they are implemented in lymphoma disease assessment?  

Dr Russler-Germain: PET-CT imaging is a dual modality imaging assessment, which both provides anatomic measurements of disease burden using the CT parameters of measuring how large by one centimeter, two centimeters, et cetera, a residual lesion is, but also has a functional component. So the 18F-FDG is a radio tracer sugar equivalent that is taken up by highly metabolically active tissues, namely cancers, for example, that allow us to assess not only how much a disease has shrunk anatomically by the CT component of the imaging, but whether it's quote unquote cold or dead even based on the PET imaging.  

We use what's called the Deauville five-point scale, which intuitively ranges from one to five, to semi-quantitatively adjudicate whether patients are in remission or not, with scores of 1 through 3 being complete metabolic response and scores of 4 or 5 being residual disease. Unfortunately, it's a little bit in the eye of the beholder as PET scan technologies evolve and are getting more sensitive, but unfortunately not reaching quite the level of sensitivity where complete metabolic responses are definitively able to prognosticate a cure.  

Kelly Conger: So it sounds like PET CT scans are a pretty well-established technology for lymphoma disease detection, but you're also getting at some of the drawbacks of this technique. Can you elaborate a little more on the limitations of PET-CT technology for us?  

Dr Russler-Germain: As great as our modern PET-CT imaging technologies are, they still only detect disease down to the two to three cubic millimeter resolution. And while certainly that is extremely helpful in adjudicating whether patients have reasonably responded to disease or not, several studies have shown that patients even with definitive complete metabolic responses have a high recurrence rate, upwards of 10 to 20%. And conversely, patients who have residual disease seen on PET scan still may have even a 50% or greater chance of being cured because of the risk of false positive signals by PET scan. And so when you factor in that there are patients with underlying low-grade lymphomas, non-nodal tissues such as the nervous system, GU system, especially testicle, as well as gastric lymphomas are very tricky to discern on PET-CTs. Improving upon our PET response assessments is a really crucial aspect in the field.  

Kelly Conger: You cited some interesting data regarding disease recurrence rates in patients with positive versus negative PET results. How good is PET-CT imaging at determining treatment response? And are there any data to show the prognostic power of this technique in lymphoma patients?  

Dr Russler-Germain: Perhaps the most robust data we have regarding the prognostic capacity of end-of-treatment PET-CT scans comes from the randomized Phase III GOYA Study comparing rituximab plus CHOP versus obinutuzumab plus CHOP in frontline DLBCL. And in this cohort of over 1,000 patients, several notable observations could be made. First, was the roughly 20% false negative end-of-treatment PET rate. In essence, patients called in a complete response still had a one in five chance of subsequent disease recurrence within three years. And secondarily, patients with end-of-treatment positive PETs had roughly a 50% chance of actually being cured, in essence, never having their disease come back despite not being in complete response at end-of-treatment. And so multiple attempts have been made to improve upon PET scans as far as our end-of-treatment adjudication goes. Some studies have looked at whether adding bone marrow biopsies are necessary or not to look for actual residual cells, and that has not panned out to be a modern standard of care. Patient people have also thought about flow cytometry-based assays, both in the aforementioned bone marrow compartment as well as in peripheral blood. But as everyone knows, DLBCL is predominantly not a peripheral blood circulating disease. And that's why in the era of next-generation sequencing and quantitative PCR, multiple non-invasive blood-based biomarkers looking for genomic alterations inherent to the disease cells are proving to be dramatically perhaps more useful than end-of-treatment PET scans.  

Kelly Conger: Wow. So it sounds like there is a real shift happening from PET-CT imaging to these more molecular-based techniques. Can you tell us a little more about these alternative methods for residual disease detection and how they are being implemented?  

Dr Russler-Germain: In the last 10 to 15 years, there have been immense strides made in using molecular biology techniques to track residual disease in DLBCL, albeit predominantly on the research side and only recently starting to enter the clinic.  

Early on, as we know from multiple other diseases, the malignant B cells in diffuse large B-cell lymphoma almost always have a canonical immunoglobulin rearrangement that could be trackable using either PCR or sequencing-based technologies. And so several assays have looked both in the circulating cell component as well as in more recently circulating cell-free DNA or circulating-tumor DNA compartment in the plasma for these prototypical or sort of barcoded immunoglobulin heavy or light chain rearrangements for tracking residual malignant B cells, often to the level of one in 100,000 circulating cells. 

More recently, with the advent of next-generation sequencing on a broad scale, such as whole exome and whole genome sequencing, we now have a better understanding of the molecular profile and commonly recurrent mutations in diffuse large B-cell lymphoma, as well as others, allowing the development of targeted sequencing panels. to identify sort of trackable variants from a patient's baseline plasma sample from ctDNA or from their actual tumor tissue. And then those same mutations can then be looked for in a subsequent analyte, such as the plasma at mid-treatment or end of treatment, for an MRD or measurable residual disease assessment.  

Kelly Conger: With the introduction of these newer sequencing technologies for MRD assessment, have there been any head-to-head comparisons with PET-CT imaging? 

Dr Russler-Germain: Each of the seminal ctDNA sequencing studies described in 2025 regarding the performance of ctDNA MRD testing at end-of-treatment in frontline DLBCL management showed a very convincing signal all in the same direction, that MRD-based prognostication at end-of-treatment outperforms PET scans. And that's not to say they aren't complementary, but what we've observed is that in multiple cohorts, the end-of-treatment positive PET patients still had roughly a 50% chance of being free from recurrence at two to three years after end of treatment, whereas patients with detectable MRD at end of treatment had only a 20 to 25% chance of remaining free from progression at two years. Conversely, the patients who had complete metabolic responses on their end of treatment PET scans still had a 10 to 20% chance of recurrence based on PET alone, whereas that risk was less than 10%, approaching even five or only 4% in some studies for patients with undetectable MRD by ctDNA sequencing. 

Kelly Conger: It's incredible to think how far the field has come in just the last decade or so. Dr Russler-Germain, thank you so much for your time today. And thank you to our audience for listening to this Oncology Learning Network segment. Our discussion today covered the evolving landscape for residual disease detection in lymphoma from PET-CT imaging to ctDNA molecular residual disease or MRD testing.