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MRD Testing in Hematologic Malignancies Other Than ALL

Panelists: Ryan D. Cassaday, MD, University of Washington School of Medicine; Mark R. Litzow, MD, Mayo Clinic; Jae Park, MD, Memorial Sloan Kettering Cancer Center; Rachel E. Rau, MD, Baylor College of Medicine
Published: Friday, Mar 13, 2020



Transcript:

Mark R. Litzow, MD: We’ve talked about how our pediatric colleagues have led the way in using MRD [minimal residual disease] testing and now we’ve incorporated it in the adult world. I’ve been impressed with how it’s infiltrating other diseases. I know my myeloma colleagues are using it more and more. I know there’s a national trial going on now in CLL, chronic lymphocytic leukemia, that’s actually going to try to use MRD to limit therapy in those patients. Up to now, take the example of ibrutinib: patients need to stay on that long-term. They’re looking at trying to shorten the duration of that. I think we know, in the adult world in chronic myeloid leukemia [CML], treatment-free remission has become a hot topic. I don’t know, Ryan, if you could comment a little bit about that?

Ryan D. Cassaday, MD: I think CML is a great example and arguably the other disease where MRD detection has become really a routine standard, an accepted approach in identifying those patients who achieve certain milestones and maintain complete molecular responses, potentially allowing them an opportunity to get off of the TKI [tyrosine kinase inhibitor] and stay in remission, knowing that if the molecular response is lost, if the BCR-ABL transcript is detectable again, many of those patients can go back on the TKI and get back into an MRD-negative state. Obviously, those are patients you have to be very mindful of and make sure that they’re reliable and they come back to their clinic appointments and they’re willing to be checked and so forth.

You didn’t mention acute myeloid leukemia [AML], but there’s certainly some established use of MRD, whether it’s NPM1 mutations where we know a little bit more about the importance of either eradicating some of these different assays or not. I completely agree that we’re going to be seeing these assays more and more in other hematologic malignancies. But, for now, ALL clearly has the biggest foothold.

Mark R. Litzow, MD: I’m going to name names here and talk about your colleague, Brent Wood, MD, PhD, who’s really the world authority both in ALL and the use of flow cytometry for measuring minimal residual disease in AML as well. One of the things I’ve learned is you can’t just automatically extrapolate what we’ve learned in ALL to AML. It’s a different fish. I don’t know if you want to comment a little bit about that, and then I want to ask Rachel to talk a little bit about that as well.

Ryan D. Cassaday, MD: I think one of the key things, one of the challenges really, is that with myeloid blasts it’s not necessarily as easy to discriminate between malignant and non-malignant blasts, and flow cytometry can sometimes be challenging. Molecular-based assays seem to be a little bit more of a desirable approach there, and with increasing understandings of different mutations that are identified in AML, it certainly stands to reason that assays could be leveraged to be used for not just diagnostic and prognostic purposes, but also response assessment.

But it’s also really important that many of these assays that are being used currently to identify the DNMT3A mutations and IDH1 mutations are not necessarily quantitative. You can’t necessarily send a repeat of that assay on a follow-up bone marrow at 21 days or post-consolidation and use that as a marker. It’s important to make sure that you’re talking to your laboratory and you’re talking to pathologists to know, is this an actual quantitative result or is this an MRD quality assay so that if nothing else, we’re not wasting money, frankly, on assays that maybe aren’t useful. On the flip side, there’s always the possibility of just detecting clonal hematopoiesis that isn’t necessarily related to the AML. You may go chasing after some mutation that actually doesn’t have anything to do with their underlying disease.

Mark R. Litzow, MD: That’s another hot topic that we don’t have time to get into, but it’s very exciting. Rachel, can you tell us about use of MRD outside of ALL in the pediatric hematology/oncology world?

Rachel E. Rau, MD: Right. We obviously don’t have patients with CLL [chronic lymphocytic leukemia] and multiple myeloma to comment on.

Mark R. Litzow, MD: No.

Rachel E. Rau, MD: We are using it in AML. I think in AML, as opposed to ALL, our risk stratification is more driven by the genetics of the tumor rather than the MRD because MRD is much more challenging, as Mark very nicely explained. In those patients who lack the clear-cut favorable or the clear-cut unfavorable cytogenetics, or anybody in between, the coin flip is their MRD status. We are incorporating it into our management of patients, and really the decision is, do they need transplant or not in first CR [complete response]? If they lack those favorable or unfavorable features and they’re MRD negative at the end of their first induction block, then they are candidates for chemotherapy alone, for instance; whereas if they’re still MRD positive, then they would be put on the arm to get a transplant in first CR. So we are incorporating it with the caveat that it isn’t quite as well worked out as it is in the ALL world, for sure.

Transcript Edited for Clarity

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Transcript:

Mark R. Litzow, MD: We’ve talked about how our pediatric colleagues have led the way in using MRD [minimal residual disease] testing and now we’ve incorporated it in the adult world. I’ve been impressed with how it’s infiltrating other diseases. I know my myeloma colleagues are using it more and more. I know there’s a national trial going on now in CLL, chronic lymphocytic leukemia, that’s actually going to try to use MRD to limit therapy in those patients. Up to now, take the example of ibrutinib: patients need to stay on that long-term. They’re looking at trying to shorten the duration of that. I think we know, in the adult world in chronic myeloid leukemia [CML], treatment-free remission has become a hot topic. I don’t know, Ryan, if you could comment a little bit about that?

Ryan D. Cassaday, MD: I think CML is a great example and arguably the other disease where MRD detection has become really a routine standard, an accepted approach in identifying those patients who achieve certain milestones and maintain complete molecular responses, potentially allowing them an opportunity to get off of the TKI [tyrosine kinase inhibitor] and stay in remission, knowing that if the molecular response is lost, if the BCR-ABL transcript is detectable again, many of those patients can go back on the TKI and get back into an MRD-negative state. Obviously, those are patients you have to be very mindful of and make sure that they’re reliable and they come back to their clinic appointments and they’re willing to be checked and so forth.

You didn’t mention acute myeloid leukemia [AML], but there’s certainly some established use of MRD, whether it’s NPM1 mutations where we know a little bit more about the importance of either eradicating some of these different assays or not. I completely agree that we’re going to be seeing these assays more and more in other hematologic malignancies. But, for now, ALL clearly has the biggest foothold.

Mark R. Litzow, MD: I’m going to name names here and talk about your colleague, Brent Wood, MD, PhD, who’s really the world authority both in ALL and the use of flow cytometry for measuring minimal residual disease in AML as well. One of the things I’ve learned is you can’t just automatically extrapolate what we’ve learned in ALL to AML. It’s a different fish. I don’t know if you want to comment a little bit about that, and then I want to ask Rachel to talk a little bit about that as well.

Ryan D. Cassaday, MD: I think one of the key things, one of the challenges really, is that with myeloid blasts it’s not necessarily as easy to discriminate between malignant and non-malignant blasts, and flow cytometry can sometimes be challenging. Molecular-based assays seem to be a little bit more of a desirable approach there, and with increasing understandings of different mutations that are identified in AML, it certainly stands to reason that assays could be leveraged to be used for not just diagnostic and prognostic purposes, but also response assessment.

But it’s also really important that many of these assays that are being used currently to identify the DNMT3A mutations and IDH1 mutations are not necessarily quantitative. You can’t necessarily send a repeat of that assay on a follow-up bone marrow at 21 days or post-consolidation and use that as a marker. It’s important to make sure that you’re talking to your laboratory and you’re talking to pathologists to know, is this an actual quantitative result or is this an MRD quality assay so that if nothing else, we’re not wasting money, frankly, on assays that maybe aren’t useful. On the flip side, there’s always the possibility of just detecting clonal hematopoiesis that isn’t necessarily related to the AML. You may go chasing after some mutation that actually doesn’t have anything to do with their underlying disease.

Mark R. Litzow, MD: That’s another hot topic that we don’t have time to get into, but it’s very exciting. Rachel, can you tell us about use of MRD outside of ALL in the pediatric hematology/oncology world?

Rachel E. Rau, MD: Right. We obviously don’t have patients with CLL [chronic lymphocytic leukemia] and multiple myeloma to comment on.

Mark R. Litzow, MD: No.

Rachel E. Rau, MD: We are using it in AML. I think in AML, as opposed to ALL, our risk stratification is more driven by the genetics of the tumor rather than the MRD because MRD is much more challenging, as Mark very nicely explained. In those patients who lack the clear-cut favorable or the clear-cut unfavorable cytogenetics, or anybody in between, the coin flip is their MRD status. We are incorporating it into our management of patients, and really the decision is, do they need transplant or not in first CR [complete response]? If they lack those favorable or unfavorable features and they’re MRD negative at the end of their first induction block, then they are candidates for chemotherapy alone, for instance; whereas if they’re still MRD positive, then they would be put on the arm to get a transplant in first CR. So we are incorporating it with the caveat that it isn’t quite as well worked out as it is in the ALL world, for sure.

Transcript Edited for Clarity
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