Harry P. Erba, MD, PhD: I want to come back to Adam. We’re running out of time on this, and we can’t do it justice, but what about using these assays, next-generation sequencing and flow cytometry, for looking at minimal residual disease [MRD]? Are we there yet? Can we use these in our clinical practice?

Adam Bagg, MD: I’ve got 3 hours to answer that question. Of course, it’s the holy grail. We all know that, and there are other diseases where MRD has been useful, like in CML [chronic myelocytic leukemia] and perhaps in ALL [acute lymphocytic leukemia]. There are emerging data on AML for sure, and there are many studies showing its value. The major issue, at least from a flow cytometric point of view—which experts can certainly do and pick up 1 of 104, or 1 of 100,000, leukemic cells perhaps using flow cytometry—is that it is largely done only in a few experts’ hands. It’s not widely available. Even when it does become widely available, there are going to be standardization issues with flow cytometry. It’s not as easy as picking up a single monoclonal CD5-positive lymphocyte in CLL, for example.

By contrast, many of the molecular assays are likely to be more useful, more standardizable, and more sensitive or as sensitive for tracking measurable residual disease. Unfortunately, not 100% of patients are amenable to molecular-based MRD testing. For those who have a known chromosomal translocation in 8;21 or chromosomal inversion 16, there are sensitive molecular assays to track disease. NPM1 mutations can be tracked quite sensitively, and we’re aware of the papers on that and on the value of finding measurable disease for NPM1 mutations.

Even in that scenario, there isn’t standardization, and there is more than 1 assay. Do you go for a quantitative RT [reverse transcriptase] RNA-based assay? Do you do a DNA PCR [polymerase chain reaction] assay? Do you do something other than the PCS assay, using droplet digital-based approaches? What about next-generation sequencing [NGS] for measurable residual disease? Unfortunately, although they again published data, most NGS panels are not sufficiently sensitive for MRD testing, but some people use it to track disease. One has to appreciate that they’re not yet quite as sensitive as some of the single-gene assays. In the future, that may change. There will be newer ways to do next-generation sequencing using duplex PCR assays, using unique molecular identifiers, or using error-corrected sequencing. These are all on the horizon, and they may allow us in the future to use NGS platforms to track MRD rather than going for single-gene assays, but we still have a way to go.

Harry P. Erba, MD, PhD: I need to let the clinicians weigh in a bit on this, and it’s a huge topic. If you don’t mind, I’m going to ask a specific question, and then you can do whatever you want, Eunice and Sasha. You give a patient with AML without a marker, without FLT3 mutation and without IDH mutation, 7+3 chemotherapy. At the end of it, you get back your blood marrow biopsy showing complete remission, but they find 0.1% myeloid blasts with a similar immunophenotype to the leukemia-associated immunophenotype. Eunice, what do you do?

Eunice S. Wang, MD: That’s the million-dollar question. If we measure minimal residual disease, what are we going to do about it? In the past, it’s like this: I’m not going to look for it because what if I find it? I’m not sure I would do anything differently. If I picked up that small amount of MRD, I would potentially enroll patients on clinical trials. There are a number of entities, particularly immunotherapeutics, looking at whether they can function as MRD erasers similar to how we use blinatumomab in ALL. In that situation, I would enroll them on a clinical trial to theoretically erase the MRD.

The other option would be if that patient is MRD positive. We all know that’s not a good thing. How many abstracts and presentations have we seen that say if you’re MRD positive, you’re going to do worse than if you’re MRD negative? How many Kaplan-Meier curves do we have to have that? In that situation, the data suggest that it’s not useful to continue to give the same type of chemotherapy. If the patient is MRD positive after 7+3 chemotherapy, would I go on to a 5+2 chemotherapy consolidation or a high-dose cytarabine consolidation? I might not because that suggests that it is an indicator of therapy resistance. If I were to continue the patient on therapy, I might switch to an epigenetic-based therapy. More likely, the better option would be that I would send them to transplant.

There are a lot of studies that say if they patient is MRD positive, then yes, they’re going to do worse with transplant. On the other hand, we’ve all been in that situation, with somebody who has 0.01% MRD. And you decide to give them more therapy to try to get rid of it. The next time you do it, it’s 1% MRD. You say, “That didn’t work. I’m going to switch, and I’m going to try something else.” The next time you do it, it’s 5%. You’re then going back to your transplant person and saying, “I was going to do this transplant a few months ago, but now they have 5% disease.” The transplanter is saying, “What are you doing? You should have sent them to us when they were 0.01% MRD. I would have transplanted them, and they would have had a better option.” We don’t have a good answer. If I see that, I’m going to try to send them to transplant if I can’t get them on a trial. Right now, that would be my way to pursue it.

To go back to what Adam was saying, I tend to believe flow cytometry is done by my expert flow cytometry team at my academic institute, Roswell Park Comprehensive Cancer Center, although that’s not standardized. Your assay getting 0.01% might be 0 at my institute, and it might be 5% at Sasha’s institute at the University of Pennsylvania Perelman School of Medicine. So there is inconsistency.

Some people say, “We’re going to use NGS, and we’re going to use the mutational marker instead. That’s more precise.” Fifty percent of people don’t have a measurable marker. Of the people that have measurable markers, there have been data presented at 2020 ASH [American Society for Hematology Annual Meeting] that for a certain percentage of patients, NPM1 was the example of a mutation that doesn’t go away. It’s a founder mutation; you can track leukemic disease by doing next-generation sequencing for NPM1. There are some data presented at this year’s meeting that a certain percentage of patients who have NPM1 positivity after induction chemotherapy will have that NPM1-positive disease go away with subsequent therapy or even with no therapy. There are a lot of trials saying, “This person turned positive by NPM1, so we need to do something.” They’re now saying, “Maybe if you did nothing, then it would go away.” We don’t know anything based on some of these techniques. It varies based on the technique and who does it.

For molecular markers, we also have the question that comes up all the time: People will look at the time of remission, and they’ll do mutational testing if they haven’t done it at diagnosis. They pick up DNMT3A mutation in the patient who has a complete remission. How do we know that’s not clonal hematopoiesis? Is that mutation diagnostic for the disease? Could it be the underlying background marrow in which the AML develops? There are a lot of questions. I’m going to turn it over to Sasha to address what he would do.

Transcript Edited for Clarity