Optimizing Circulating Tumor DNA Limits of Detection for Patients With Diffuse Large B-Cell Lymphoma During First Line Therapy
In this video, Mark Roschewski, MD, discusses the key points from his team’s research that investigated the value of circulating tumor DNA when treating patients with diffuse large B-cell lymphoma (DLBCL). Dr Roschewski speaks about the current and emerging technology being used in treatment, and what knowledge gaps remain in this area of research. The results of the study were presented at the American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.
Additional Resource:
Goldstein J, Kim WS, Yoon SE, et al. Optimizing Circulating Tumor DNA Limits of Detection for DLBCL during First Line Therapy. Paper presented at: American Society of Hematology's Annual Meeting & Exposition; December 9-12, 2023. Accessed December 13, 2023. https://ash.confex.com/ash/2023/webprogram/Paper187759.html
For more coverage of ASH 2023, visit the newsroom.
TRANSCRIPTION:
Mark Roschewski, MD: My name is Mark Roschewski. I'm a clinical investigator who works here in Bethesda, Maryland at the National Cancer Institute, taking care of patients exclusively that have various forms of lymphoma.
Consultant360: Please give an overview of the study entitled, “Optimizing Circulating Tumor DNA Limits of Detection for DLBCL during First Line Therapy.”
Dr Roschewski: This is an abstract that's part of a greater effort that I'm involved in to try to understand the best way we can use, in this case, circulating tumor DNA, to determine how effective our therapy is in the frontline therapy for patients with aggressive B-cell lymphomas. So what this refers to is that when we're giving therapy to these patients, the best way we know how to assess the response is by using imaging scans. But those imaging scans are insensitive. They can't pick up disease at what we might think of as the molecular level or below the level of detection. And so there's an emerging technology known as cell-free DNA, which actually is little shards of DNA that are floating in the bloodstream that actually come from the tumor, and that can be measured as a noninvasive way to have a sense for the actual amount of tumor load.
So you can imagine that when you're giving somebody therapy, what you want to know is how those measures of tumor load have changed. In other words, are they completely gone at the end of therapy? Can you tell that they've been reduced or significantly reduced after just two cycles of therapy? And this has been an effort that's been ongoing for about eight years to understand what is the optimal threshold, or how low do you have to go after just two cycles of therapy or at the end of therapy actually to be able to detect residual disease? Because in these lymphomas, if you have residual disease when therapy is supposed to be over, that means that relapse is imminent.
C360: How do the results of your study impact the treatment of patients with DLBCL?
Dr Roschewski: They don't have an immediate impact on the treatment. What this is, is additional data to help underscore the value of circulating tumor DNA. So what that means is that we envision a day in which we can actually assess response in a formal way by the presence or absence of these amounts of cell-free DNA at the end of therapy. If we can improve the way we determine if patients are actually in remission, we can do two things. One is we can actually prioritize salvage therapy, second-line therapies only in patients that actually have disease as residual, and we can avoid monitoring patients who've already cleared their circulating tumor DNA at the end of therapy. In other words, they've already been cured or they're in remission. We have to improve the ways we define remission because the way we do it now, our tests are only about 50% accurate at actually determining whether our patient is actually in remission even at the end of therapy.
C360: How does this study fill current knowledge gaps in this area of research?
Dr Roschewski: What we're talking about now is that the technology being used in this study, which is known as PhasED-Seq, actually has improved sensitivity and improved limits of detection compared to previous versions of circulating tumor DNA. So when we've used previous versions of circulating tumor DNA that don't have the same analytical sensitivity, then what we see is that they do a pretty good job of detecting circulating tumor DNA at the beginning of therapy and even in the middle of therapy. But when you get to the end of therapy when there's only very small levels of residual disease left, if at all, then you really can't detect it unless you use technologies that have an analytical sensitivity that's much lower. And this is an example of that.
So PhasED-Seq is the name of the assay, and because that has improved analytical sensitivity, we might categorize it as ultrasensitive assays for circulating tumor DNA. That then introduces the ability to measure it at the end of therapy because now you're much more confident that if you don't detect it, that the disease is truly gone. And so this is where the knowledge gaps have been. In other words, how low do you really have to be able to detect at the end of therapy to be certain that you don't have residual disease? And it looks like 10 to the -6 or greater as far as a limited detection is actually needed at the end of therapy to be certain that you've eradicated the disease.
C360: What knowledge gaps remain?
Dr Roschewski: There's a lot. I mean, when you have cell-free DNA, circulating tumor DNA, one of the benefits is that it's such a versatile analyte, which means it could be tested in a number of different settings. It can be tested earlier in therapy. We even now know that before you even start therapy, there's prognostic value and that only refers to that particular lymphoma. There's multiple different other lymphoma subtypes that these technologies still need to be developed in. In other words, if the goal is something different than cure, if we're treating patients that have something else, like for example, follicle lymphoma, it may not be as critical that you get to such low levels of disease because in most cases, we sort of anticipate that those patients will have disease that relapse at some point. Whereas when we're treating aggressive lymphomas, of course, that could be the difference between cure or not.
So these are the types of questions that will continue to be asked across various lymphoma subtypes, and we haven't even started thinking about better ways of monitoring patients who have not achieved remission. This becomes a noninvasive way to actually follow patients in the clinic. And there could even be a day in which we actually decide that we want to start a new therapy based on the presence or absence of disease in this way. It's also possible that we can find the reasons why patients will actually relapse. In other words, the mechanisms of resistance might be teased out by using these noninvasive blood-based tests. These are all questions that will continue to be asked in this lymphoma and others, and I think that this will just continue to be sort of a merging field as it relates to lymphoma.
C360: What is the overall take-home message from this study and presentation?
Dr Roschewski: I think the number one take-home message is that this particular assay really does have improved analytical sensitivity, this PhasED-Seq. Why that's critical is principally at the end of therapy. We have not yet seen other assays show the same level of performance. So that's true. In other words, not all assays of MRD are created equal, and it's particularly important at the end of therapy. In other timelines, it may not be quite as important. So I think the take-home message is that, and that you should continue to expect emergence of this technology. It's an emerging technology, so we'll continue to see other companies or other assays that try to hit the same benchmark. I think that's what you're going to find from these types of data.
Again, I'd like to thank everyone for listening to this. This is a fun topic to talk about, how we might use circulating tumor DNA. I hope that it has been informative as we all are learning how to best use this to improve the outcomes for our patients.