The Use of Circulating Tumor DNA in Lymphoma
In this video, Mark Roschewski, MD, discusses the key established principles in circulating tumor DNA (ctDNA) in lymphoma, including using ctDNA in prognosis, as a measure of tumor burden, and acting on residual disease at the end of therapy. He also discussed these topics at the SOHO 2023 Annual Meeting during a session titled “Circulating Tumor DNA in Lymphoma: When Will This Be Ready for Prime Time?”
Roschewski, M. Circulating tumor DNA in lymphoma: When will this be ready for prime time? Talk presented at: The Eleventh Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). September 6–9, 2023. Accessed September 7, 2023. sohoonline.org
For more SOHO 2023 Annual Meeting coverage, visit the newsroom.
Mark Roschewski, MD: My name is Mark Roschewski. I'm a clinician, a clinical investigator focused on lymphoma, and I work at the National Cancer Institute here in Bethesda.
Consultant360: Please provide an overview of your session at the SOHO 2023 Annual Meeting titled “Circulating Tumor DNA in Lymphoma: When Will This Be Ready for Prime Time?”
This is a topic that is discussed a lot at meetings, and what we're basically saying is how do we envision developing these newer assays, these circling tumor DNA assays, to help us actually make decisions as we treat patients with lymphoma? So this principle has been around for maybe five or seven years, which is to say we actually know that we can measure the free-floating DNA in the bloodstream, and this DNA is coming from the lymphoma cancer cells. So we're not actually measuring the cells, we're measuring the tumor-specific DNA that's just floating in the bloodstream. We know that that exists, but the question is, well, how do we use that to tailor our treatments?
And so what the talk is going to be about is... The way I set it up is this is a developing field, so what have we learned so far? So what are the fundamental principles that we've learned that are unlikely to change that we can build upon based on previous studies to actually get to the clinical utility? And then, what are sort of the most important questions now, and what are the potential down the road once we answer the questions now? So one of the things that we would do in this situation is say, well, where is the potential utility the greatest? So a number of studies have shown us that these assays can be a pretty good marker of disease activity, and that might be useful at the beginning of therapy and potentially in the middle of therapy. But where it really probably is going to make the most difference is at the end of therapy or when you think you're done with therapy.
So, there are other aggressive malignancies that do this. So acute leukemias do this. These are examples of curable malignancies in which the chemotherapy can cure a large percentage of patients. But in the situations where you don't cure them, what's happening is there's residual disease that you just can't measure with normal means. And that's sort of where we're focused now, in at least diffuse large B-cell lymphoma, is can these new assays actually measure disease when your PET scans are completely negative?
We know there's a big opportunity here because the PET scans really can't measure disease down at the molecular level. Any imaging test requires that there be... something shows up on a CAT scan, and a one-centimeter tumor is 1 billion cancer cells. So what we're talking about is how do we measure down below that limit of detection, and can these be used? Because in a situation in which you've already delivered your therapy, if you see that there's still persistence of ctDNA, then the chance of that patient relapsing is extremely high. It may not be a hundred percent, but it's pretty close to it. So that's what we're trying to do is envision a time in which we're actually acting on residual disease at the end of therapy.
C360: What are the key established principles regarding ctDNA in lymphoma?
Dr Roschewski: One of the things that we've learned is that these assays are extremely tumor-specific, and that's a big feature of them. In other words, these are fragments of DNA that are present in the original tumor. So when they're there, they're almost always related to tumors, whereas results on imaging scans, they're not very specific for lymphoma. You find all kinds of things, whether it's inflammation or other cancers or other features within the patient that have nothing to do with lymphoma, so they can mislead you. And these scans are the basis of our response criteria. So when we say a patient didn't achieve a complete response, we might be measuring something that has nothing to do with lymphoma. So that's one important fundamental feature, is that they're very tumor-specific.
And then the other thing is, or a couple of other things, they have a very short half-life. So the DNA, we're talking about a half-life that's only measured in a few hours. So they're a really rapid readout. We've even seen that after one or two cycles of therapy, they can become prognostic. So you don't actually always have to wait until the end of therapy. You could actually measure things after one cycle or two cycles. And this seems to be true that that's prognostic. It may not be as prognostic as it is at the end of therapy, but you can envision a situation where you change therapy based on the fact you don't reach a certain benchmark, as we've seen in things like chronic myelogenous leukemia, where if you don't hit your benchmark, maybe you switch therapy. Those are at least testable hypotheses.
And it does seem that these are related to tumor burden. So they're a pretty good measure of tumor burden. That's not the whole story. There are other things associated with it, but they're a pretty good measure of tumor burden. So at the beginning of therapy, they can actually be used as prognostic information. In other words, when you have really high levels of circling tumor DNA, at least in large cell lymphoma, it's actually a poorer prognosis than if you have lower levels of circulating tumor DNA. This is more prognostic than typical features. So it's not just what you might get from an IPI or even total metabolic tumor volume on a PET scan. These seem to have independent prognostic information. So I think we've learned those things, at least in large-cell lymphoma. They look like they're also true in Hodgkin's lymphoma, but we know a lot less about some of the other lymphoma subtypes.
C360: Please discuss some key studies in diffuse large B-cell lymphoma.
Dr Roschewski: We did a study in 2015 in which we looked at the VDJ sequence, and that was our circulating tumor DNA assay. And that was one of the first studies that showed this relationship to tumor volume. It showed that levels changed during therapy, and it showed that even after therapy, it's not uncommon at all for you to pick up evidence of disease in the bloodstream before it ever shows up on a CT scan. So we showed that. Also, the group at Stanford showed a very similar thing with therapy with the same assay. They showed that it was the acellular portion of the blood, in this case, plasma, that was much more predictive than the cellular component. They showed the correlation with PET scans, and they showed that these changes during therapy were actually prognostic. So those have been key studies.
Now, there have been some pooled analyses that did a little bit better job at putting some fine-tuning to this. So there was a study published in the Journal of Clinical Oncology in 2018 by the Stanford group, and they put a number of studies together in frontline therapy with large cell lymphoma, and they were able to show that certain benchmarks that they labeled either early molecular response or major molecular response, which was the difference between after one cycle and two cycles of therapy, that those were indeed prognostic. This had to do with the log fold change, so an individual change from where you started to after a cycle or two cycles of therapy, looking at these benchmarks. And they were able to show that that indeed was prognostic. Now what we've been working on more recently is at the end of therapy. So those are some data we've presented, that we've not yet published, looking at the truest MRD, which is to say, after therapy is completed, do you still have residual disease? And so those data are coming out, but they aren't published yet.
C360: Please discuss some key studies in Hodgkin lymphoma.
Dr Roschewski: Hodgkin lymphoma has similarities, but also some key differences. So the similarities are that it looks like those principles also apply to Hodgkin lymphoma. Hodgkin lymphoma is also an aggressive lymphoma. It also is frequently cured with chemotherapy. And so it does look like the baseline levels are prognostic. It looks like changes after one or two cycles are prognostic. And it's even possible that at the end of therapy, there's some prognostic utility. Now, that's pretty important in Hodgkin lymphoma because there are really no circulating cells in that situation. So it's also a similar situation where it has to be the cell-free DNA. There's no way of doing a marker looking at tumor cells because Hodgkin lymphoma doesn't circulate.
The biggest difference though is the cure rate for Hodgkin lymphoma is so much higher. So now with most recent studies, we're seeing that the cure rate is pushing over 90% and maybe as high as 95% in some groups of patients. So what that brings up is, what is the truest need of MRD if you're curing most of the patients? It's probably going to be to start limiting some of the therapy, to maybe not give radiation to certain groups of patients independent of PET scans, some of these other kinds of things that might benefit patients as far as toxicity. Those studies are probably the next step, but it looks like these assays can help inform some of these clinical decisions, both in the clinic and in research.
C360: What is next for research on ctDNA in lymphoma?
Dr Roschewski: One thing I like to point out when it comes to this assay is it's an emerging field. So just like our computers, we anticipate this getting better. So even the assays we're using now are significantly better than the assays we used five years ago. And so I think this is a technological advance, whereas we get better at these things, they will be better tests. Also, as we implement this into our agendas or the way we do medicine, the way we collect these and store them and process them, that isn't part of how we do things at this point. So that's kind of a learning curve that has to be developed. But the benefit is that it looks like it's applicable across therapy, so it's not tied to any specific therapy. So it doesn't look like the prognostic value is only seen in chemotherapy or only seen with immunotherapy, or only seen with targeted agents. At least the studies that have been done so far, it looks like it's prognostic across these therapies.
So one of the things we're dealing with in oncology and lymphoma right now is all our therapies are changing. We're using new combinations. We're using novel immunotherapies that might cure patients. But it does look like these maintain that value no matter what therapy you use. And so really, the benefit is kind of broad. It goes across all of these different therapies, and it can continue to be sort of a solution to a lot of problems as our therapies continue to emerge. So that's one thing that may not be obvious at the beginning is that this is probably a new paradigm for how we're going to think about measuring disease that doesn't currently exist.
C360: Is there anything else you would like to add?
Dr Roschewski: The one thing we didn't talk a lot about is how this applies to all the different lymphoma subtypes. So there are a lot of different lymphoma subtypes, and the goal of therapy can be quite different. So I spent most of my time in this talk, I spent most of my time thinking about aggressive lymphomas where the goal is cure. But there's a whole nother group of patients that have indolent lymphomas, where the goal isn't necessarily cure. It's maybe to induce remissions that last a long time. And so there, the role of these things might be quite different. It might help us tease out what therapies are better within the context of clinical trials, but it also might provide us with opportunities to stop therapy.
So one of the things we do with follicular lymphoma, for example, is we give therapy, and then we give maintenance therapy for years on end, but we don't even know if it's required to give therapy for that long of time. So sometimes these additional ways of measuring disease that don't require scans allow us to actually test hypotheses like, well, why don't we stop therapy? Why don't we stop therapy and see if we can preserve some of the risk and toxicity in situations? That's been done in CLL, that's been done in CML. And those are other types of questions that can be asked when you use these assays. They're easy to draw. It's much easier to do a blood test than is to put someone through a scanner.