Assessing End-Of-Treatment Response for Aggressive B-Cell Lymphoma After Frontline Therapy
In this video, Mark Roschewski, MD, discusses the results of his team’s study of the use of PET/CT scans to assess remission status in patients with aggressive B-cell lymphoma. Dr Roschewski presented these findings at the American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.
Additional Resource:
Roschewski M, Lindenberg L, Mena E, et al. End-of-Treatment Response Assessment after Frontline Therapy for Aggressive B-Cell Lymphoma: Landmark Comparison of a Singular PET/CT Scan Versus Ultrasensitive Circulating Tumor DNA. 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/Paper180007.html
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TRANSCRIPTION:
Mark Roschewski, MD: Hi, my name is Mark Roschewski. I'm a clinical investigator. I work here in Bethesda, Maryland, at the National Cancer Institute, and me and my team take care of patients exclusively on clinical trials, but patients all that have various types of lymphoma.
Consultant360: Please give an overview of your presentation entitled, “End-of-Treatment Response Assessment after Frontline Therapy for Aggressive B-Cell Lymphoma: Landmark Comparison of a Singular PET/CT Scan Versus Ultrasensitive Circulating Tumor DNA.”
Dr Roschewski: We present an abstract here that is showing the results of assays for circulating tumor DNA as they are prognostic compared to PET scans within the context of a prospective clinical trial treating patients with aggressive B-cell lymphoma. So what that means is that this is a prospective trial. We're testing the ability of acalabrutinib to be added to chemotherapy, and of course, the goal of this therapy is cure. So this is an anthracycline-based chemotherapy, and the goal is to cure these patients. What we know is that our ability to assess whether or not they're in remission at the end of therapy is limited by the fact that our imaging scans don't have sufficient sensitivity. So we've shown data like this before. What I mean by that is, when we want to know if someone's actually in remission or has achieved a complete response, our assessment relies very heavily on imaging scans, the most important being the result of the PET/CT taken at the end of therapy.
Now, PET/CTs are the standard, and they're the standard way that we assess response because they're much more sensitive than CAT scans, for example. So they do serve a very important purpose. The problem is that they're not sufficiently specific for lymphoma. In other words, we know that they're prognostic, but it's only half the time when there's a PET scan that's positive at the end of therapy that it actually refers to lymphoma. And many of the patients that have a quote, "positive PET scan" when you apply the current criteria actually don't have lymphoma at all. It might be inflammatory tissue, another malignancy, or something that is unrelated altogether. So what we were interested in doing is assessing a singular time point. So if you just look at one PET scan and compare it to one blood test, in this case, circulating tumor DNA. The reason I say it that way is because since all of us clinicians know that the sensitivity of a singular PET scan and the positive predictive value is not high enough, we frequently have to do additional procedures.
Dr Roschewski: We have to do either a biopsy of a PET-avid lesion or maybe we have to repeat our PET scan just to know whether or not the patient's in remission. So it's actually a little bit of a misnomer to even think that a singular PET scan can typically tell us if we're in remission. So we did that in this analysis. We compared in a blinded way. We had nuclear medicine doctors assess the PET scan, apply the current response criteria to it, and then also blinded. We sent off an assay to Foresight Diagnostics to test for circulating tumor DNA. What we found is that almost every time the PET scan was positive, we had 15 such positive PET scans. Only two patients actually progressed. And so in most cases, almost all the cases, patients that had a positive PET scan had something other than lymphoma at the end of therapy. So this was not prognostic, certainly not compared to circling tumor DNA, which was highly prognostic, and most patients that had a positive test at the end of therapy actually progressed.
And almost every single patient that had a negative test did not progress, at least to the point we had followed him to this level. And that was a very important finding, showing that most of the time, at the end of therapy, a positive PET scan is related to something other than persistent lymphoma.
C360: What were the results of your study?
Dr Roschewski: Well, I sort of went to the point of it there, really, at the end of therapy, was the focus. What we saw was that the circling tumor DNA was the most prognostic, and it was more prognostic than PET scans. And what we saw was, even in patients in which you did a tissue biopsy afterwards, most of the time that wasn't active lymphoma, suggesting to us that these more sensitive, ultra-sensitive assays for circulating tumor DNA actually have an advantage compared to PET/CT. Now, what's new about that is, these assays are more sensitive. They have an analytical sensitivity that's better than other circulating tumor DNA assays that we've tested. And I think that actually is what makes the difference. The other thing we saw in this study was that if you looked in the middle of therapy, so only after two cycles, that was also prognostic for outcomes, but not nearly as prognostic as when you look at the end of therapy, that it seems to be the best time point to do the assays for circling tumor DNA.
C360: Why are these data points important to the study?
Dr Roschewski: There's been a long effort to about seven or eight years to try to develop these assays to improve upon the holes we have in our response criteria. So this is a known problem, but we just haven't had anything better that can actually give us an answer of whether or not there's still residual disease. So this is part of an emerging effort to continue to generate data across multiple different clinical trials showing that these assays are more sensitive and potentially even more specific than PET scans. One thing that's important here is, since the results are so critical, you might end up taking another patient that, you think, has active disease, you might take them on to get salvage chemotherapy, is we want to make sure we're not taking patients to salvage chemotherapy or CAR T therapy as part of second-line therapy that actually don't have active lymphoma at all, that would result in unnecessary overtreatment of these patients. So that is the focus of trying to improve our ability to improve the response criteria.
The only way we're going to be able to improve the response criteria is if we have larger data sets that show this is indeed prognostic and predictive of clinical outcomes.
C360: How do the results of your study impact clinical practice?
So they don't have immediate impact on clinical practice. These assays are not yet available. Mostly, they're still a research test. It's important that active clinicians, practitioners realize these tests are coming, and when they ultimately are part of the response criteria, we hope we envision that someday that they can learn how these might be used. But we have not yet established is that the treatment of active circulating tumor DNA actually improves clinical outcomes, but that becomes a testable hypothesis. In other words, when you can show that these blood tests are more predictive than imaging scans, that then becomes something that can be tested in the context of a clinical trial. In other words, does eradication of that MRD, prior to clinical outcomes, does that actually improve the ability to cure the patient? Or is it simply just introducing therapy earlier? That becomes a testable hypothesis, and there are clinical trials being designed now to try to address that what we might consider clinical utility that's not yet been established.
C360: What is the overall take-home message from your presentation?
Dr Roschewski: I think the most important take-home message is that we should not think of the response criteria as a singular PET scan. In over 30% of the times, we had to do additional tests just to figure out if the patient was in remission. So the bar is actually very low. These PET scans, as good as they are, are in the response criteria because they're better than CT scans, but they are not that specific. And so that leads us clinicians to do additional tests, additional tests that have risk to patient, to increase the cost of medical care. So these are additional PET scans, tissue biopsies, and these types of things. The other take-home message is that one should probably almost never take a patient to second-line salvage therapy without proving that there's active disease with a biopsy. What we saw in our study was that only about one out of seven times was this actually active lymphoma.
And most of the time, when you thought the patient had a positive PET scan, which would mean they're refractory to therapy, in most cases, they were actually already in remission. But the test was misleading. And so I think clinicians have to recognize the limitations of these PET scans and not just to whisk them off to second-line therapy just on the basis of a singular PET scan alone. I think they can make the mistake of overtreating too many patients if they take that approach. I hope this was informative. Thank you for your time. I know this is a subject everyone wants to learn more about, and I do think we'll continue to have these discussions moving forward. This is an exciting time for not only therapy but also the ways that we monitor response. And again, I hope this was something you find useful, and ultimately, we'll be coming to clinical practice very soon.