Pharmacy Times interviewed Reid Merryman, MD, clinical investigator and assistant professor at Dana Farber Cancer Institute in Boston, on his presentation at the SOHO 2024 Annual Meeting on the role of minimal residual disease (MRD) in lymphoma. Merryman explained the evolution and applications of MRD testing in lymphoma, particularly in relation to the use of circulating tumor DNA (ctDNA) assays.
Pharmacy Times: What was the focus of your presentation at the SOHO 2024 Annual Meeting?
Reid Merryman, MD: I talked about [MRD] and lymphoma, which is a very big topic. So [MRD] is not a new concept in lymphoma. We've had tests like flow cytometry and polymerase chain reaction (PCR), but they were limited to certain lymphoma subtypes that had circulating disease or stereotypical chromosomal rearrangement. But with development of next-generation sequencing, we were able to track ctDNA for all lymphoma subtypes.
Over the last 10 or 15 years, we've seen a trend that by tracking more tumor reporters, we’re able to increase the sensitivity of assays. So I talked about the evolution of assays that we've seen, starting with clonoSEQ, which is an example of immunoglobulin-based, high-throughput sequencing, where we track 1 or maybe a few tumor reporters, and then panel-based assays like [CAPP-Seq (cancer personalized profiling by deep sequencing)] or the AVENIO assay, where we're tracking often dozens of tumor reporters, and then the most recent ctDNA assays, like PhasED-Seq or whole-genome sequencing based assays, where we're tracking hundreds, or even in some cases thousands, of tumor reporters. With each of those steps, we've seen increased sensitivity.
There's a lot of excitement now about using these very sensitive MRD tests to help guide therapy. We're seeing some of the first MRD-guided trials where we're actually changing therapy based on MRD results in lymphoma. One example, in mantle cell lymphoma, there's a phase 3 trial which guides consolidation with transplant based on MRD status. We're also seeing trials in large cell lymphoma that are guiding intensification of frontline treatment based on interim MRD status.
Then I talked about how ctDNA can be used for goals other than renumeration of MRD, so we can actually learn about the biology of a tumor based on a plasma sample. There are some exciting data looking at identifying lymphoma subgroups based on ctDNA. You can identify the LymphGen classification among patients with diffuse large B cell lymphoma, with similar results seen from plasma and tissue, and similar results for Hodgkin lymphoma, which is a tough one to analyze using tissue because of the rarity of tumor cells.
Then there's some exciting data looking at gene expression, so we can actually infer gene expression based on ctDNA, and that may help us to identify patients with double-hit lymphoma, or even potentially transformation of an indolent lymphoma into an aggressive lymphoma, which is clinically a very important question. With all these advancements, I think there's a lot of excitement about in the future, potentially using ctDNA to help guide our therapy for our patients in the clinic, although we're not quite there yet.
Pharmacy Times: How is MRD assessment used in clinical trials currently?
Merryman: A lot of trials are tracking MRD. I would say almost all trials now have are building a collection of plasma samples so that they can look and see how MRD changes with treatment.
We're just starting to see trials that are using MRD to guide therapies, and I think there's a few different ways that MRD can be used. So we can look at changes in MRD at an early time point and then use that to either de-escalate therapy or escalate therapy, depending on the MRD status. Or we can use it to guide consolidation, like that mantle cell lymphoma trial I talked about—at the end of treatment, we can look at MRD results and decide whether we should or should not do additional treatment. There are also some trials that are testing MRD serially and using that to decide when we can stop treatment, and in some cases, when we should restart treatment if MRD emerges. So those are kind of 3 patterns of trials for how to use MRD.
Pharmacy Times: What are some research advancements in MRD monitoring techniques?
Merryman: There's a lot of excitement about the newer MRD techniques that I mentioned that are using higher numbers of tumor reporters to improve sensitivity. I think having a highly sensitive test is important when you're thinking about changing therapy based on a treatment, and I think one of the things I talked about yesterday was that there may not be a single MRD test that's best for every situation or every lymphoma subtype. We may have a situation where we're using different tests for different lymphomas depending, for example, on the frequency of phase variants or using different tests at different time points to get at different questions, like some tests are best used to identify the amount of ctDNA and other tests will help us to learn more about the biology of a tumor.
Pharmacy Times: What is the significance of MRD in different subtypes of lymphoma?
Key Takeaways
- Advances in MRD Testing for Lymphoma: Minimal residual disease (MRD) testing has evolved significantly with the development of next-generation sequencing and circulating tumor DNA (ctDNA) assays, increasing the sensitivity and applicability of these tests across various lymphoma subtypes.
- Clinical Impact of MRD-Guided Trials: Emerging clinical trials are beginning to use MRD status to guide therapy decisions in lymphoma, including treatment escalation or de-escalation and consolidation, as well as for determining when to start or stop therapy based on MRD levels.
- Future of Personalized Lymphoma Treatment: While MRD testing is not yet widely used to guide lymphoma therapy, ongoing research and trials are paving the way for more personalized treatments, with ctDNA assays offering insights into tumor biology and potentially transforming clinical decision-making.
Merryman: Right now, we have the most data for MRD and diffuse large B cell lymphoma, which is the most common lymphoma subtype. We're seeing more data in other lymphoma subtypes too, and I'm expecting to see large analyses in Hodgkin lymphoma, and I think other lymphoma subtypes, like follicular lymphoma, will see more MRD data soon. As I said, before you know these lymphomas are have different biologies and will likely have subtly different tests to assess one lymphoma subtype vs another.
Pharmacy Times: How should MRD be integrated into the treatment decision-making process?
Merryman: I think that's a moving target. Right now, we have a small number of trials that are using MRD to guide treatment decisions. We'll have more trials in the future, and the way that we use MRD to guide treatment decisions will depend upon the results of those trials.
Pharmacy Times: What are the challenges in standardizing MRD assessment across different centers?
Merryman: There are a lot of different MRD assays that are in use, and probably even more MRD assays that are in development. If we have a trial that uses one MRD assay, is it generalizable to another one, which might work differently or target different genes, for example? I think it will be important to identify a single assay, at least for a single clinical scenario, that we can agree upon using by that time. In order for us to use this in the clinic, we'll need to have a single assay for a single scenario that we all agree to use, which will be guided, I think, by those trials that I mentioned.
Pharmacy Times: What is a key takeaway from your presentation at the SOHO 2024 Annual Meeting?
Merryman: I guess the key takeaway would be that we've seen really unprecedented advances in ctDNA assays in the last 10 years, and now we're at the beginning of learning how to use those ctDNA assays clinically. I think the next step will be to have these trials that show that ctDNA can be used to personalize therapy and hopefully improve outcomes for our patients.
