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Therapy Options for MRD-Positive AML

In this video, Drs. Richard Stone, Courtney DiNardo, and Eunice Wang discuss therapy options for minimal residual disease (MRD)-positive acute myeloid leukemia (AML). The case is a 44-year-old man with no past medical history who presents with fevers and fatigue. He is diagnosed with AML and achieves morphologic remission after treatment with 7+3 (cytarabine/daunorubicin) plus gemtuzumab; however MRD flow cytometry reveals 0.1% blasts, which persists after consolidation with high-dose cytarabine. The faculty discuss how they would approach the next steps for this patient and the importance of reducing the disease burden prior to the initiation of allogeneic stem cell transplant.


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Transcript

Dr. Stone: Welcome to The ASCO Post Roundtable Series on Updates in Acute Myeloid Leukemia. I'm Dr. Richard Stone, chief of staff and director of translational research in the Leukemia Division at Dana-Farber Cancer Institute in Boston, Massachusetts. Joining me today are two of my esteemed colleagues. First, Dr. DiNardo? Dr. DiNardo: Hi Courtney DiNardo in the Leukemia Department here at MD Anderson in Houston, Texas. Dr. Stone: And Dr. Wang? Dr. Wang: Eunice Wang from the Leukemia Service at Roswell Park Comprehensive Cancer Center in Buffalo, New York. Dr. Stone: Thank you, Courtney and Eunice. Today we'll be discussing new updates in AML, including recent data presented at the 2021 American Society of Hematology Annual Meeting. And we'll be integrating as possible these new developments into four patient case studies. Our fourth installment will focus on a patient presenting with fever. So this is a 44-year-old gentleman without past medical history who's having fevers to 103 and fatigue. His white count is 31,000 with 62% blasts, hematocrit 26% and platelet count is 30,000. On peripheral blood flow, he's CD33 positive and HLA-DR negative, but cytogenetics show translocation between chromosomes 8 and 21. On the NGS panel, he has no mutations. So for induction therapy, he receives daunorubicin and cytarabine, in a 3+7 fashion, along with gemtuzumab ozogamicin, achieves a morphologic remission after one cycle, but at the time remission's achieved, he still has 0.1% blast on an MRD flow panel. But his RUNX1-RUNX1L transcript is not detected. He goes on to receive a cycle of consolidation with high-dose ara-c, but his marrow at the recovery from that cycle shows exactly the same findings: MRD flow positive, fusion transcript negative. So what do we do now? We could change the chemotherapy regimen as in choice A with mitoxantrone/etoposide/cytarabine. We could change the chemo regimen to FLAG-IDA-venetoclax, as in choice B. We could go directly to allogeneic stem cell transplant. We could give gemtuzumab, choice D. We could use azacitidine and venetoclax, choice E, or we could even use oral azacitidine, choice F. So this is a challenging case and really with no easily chosen answer, but I would like to know how Dr. Wang handles patients like this who received a good deal of chemotherapy, still in remission, but are MRD positive by one means or another, or both. Eunice? Dr. Wang: So this is a challenging case because this is a younger patient with what we would call favorable risk, who has evidence of morphologic remission but now has MRD-positive disease, and more challenging, the MRD appears to be positive only by flow, but not by molecular, which sort of highlights why or the rationale for using both methods in some of these patients. So MRD-positive disease we know is almost inevitably associated in a huge meta-analysis with worse survival, independent of what method you use. So the fact that it's flow and not molecular really does not necessarily mean that that's better or worse. I think that there have been studies that have shown that collectively using both is even more predictive if you're positive by one or another than being negative by just one technique. In terms of what we do here, I think many of us would be concerned that this patient has received standard of care chemotherapy with cytotoxic agents and has not achieved a clearance. So I think in this setting, additional therapy would be warranted. And my thought process would be to give additional therapy and potentially think about a transplant for this young patient. Now allogeneic stem cell transplantation is preferred. And I think there are some studies actually for favorable risk disease that say that even autologous transplantation might be an option for these patients. But I think a transplant for this young patient in the future would most likely be something I would be considering. And the question would be how to get them there. One could give high-dose cytarabine consolidation with gemtuzumab, but I noticed that the first cycle of consolidation did not have gemtuzumab. However, if you're thinking about doing a transplant, particularly myeloablative, you probably would like to avoid the gemtuzumab within a couple months of a myeloablative regimen. So I think oral azacitidine could be something that you do, or you could switch venetoclax/azacitidine for these patients that are CBF leukemias. In the presence of a c-KIT mutation, people have actually also used KIT inhibitors such as dasatinib or I think there are studies now looking at avapritinib for those patients. But I think that additional therapy may be warranted. There was data presented from the QUAZAR study, the randomized phase III study of older patients 60 and above who had achieved a morphological CR and some amount out of consolidation, that the addition of oral azacitidine maintenance may have converted some MRD-positive patients in that setting to MRD negative. However, I think that the jury is still out whether there is any effective MRD erasers for the treatment of AML. Unlike what we have in ALL; that is a burgeoning field. And I think many of my colleagues and in our center as well are interested in using, for example, bispecific antibodies or immunological agents in this setting to eradicate the MRD, similar to what we do with blinatumomab in acute lymphocytic leukemia. But I think that aside from going to a transplant, the question really is to change or add to the modality of therapy to try to potentially make them MRD negative. And that brings up the question, do they need to be MRD negative before they go to transplant? I don't think so because we have no effective MRD erasers. One could argue the patient should just go to an allo transplant right now. However, my transplant colleagues will often be uncomfortable with that because they know going into transplant, MRD positive, the outcomes are not great. So I don't think we have a perfect answer. I'd be interested in hearing what Dr. DiNardo and Dr. Stone have to say in this challenging case. Dr. Stone: Absolutely. So you covered all the points very well, Eunice, but I'll ask Courtney to answer in this fashion. So when the patient presented, we probably thought, well, we could cure this patient with chemotherapy. And now because of a couple of relatively new tests, namely multiparameter flow cytometry looking at small clones of disease, we're about to tell the patient that need to have a transplant. And then we can debate about whether they go right to transplant or get something first. Courtney, is that the way you look at this case too, or do you look at it somewhat differently? Dr. DiNardo: Yeah, no, I think you're exactly right. Because I had actually a couple things I wanted to say and Eunice said them all. So she did a fantastic job of recapping exactly what I would be thinking about. So I thought, I would say just taking a step back, I think it's really interesting how both of you said this is a really challenging case, and it's only a challenging case because we've been monitoring MRD in this patient. Otherwise we would have been none the wiser, right? This is a 44-year-old patient with core-binding factor leukemia. Has had an induction in a consolidation cycle and is in a remission. Like, that's exactly what, 10 years ago, we would've been thrilled to see, but now we know that patients who are persistently positive have inferior outcomes. And these are the patients who with favorable risk that we should be thinking about a transplant for. And then you get into the nuances, which gets into the weeds very closely very quickly because we don't really know what the best thing to do in a situation like this is. But we know that based on this case story that the patient had had residual MRD by flow, and then you gave a cycle of cytarabine-based consolidation and that didn't change the MRD at all. You're not kind of getting one log deeper remission or things. So giving more consolidation, we might extend his remission a little bit, but we're not getting to that deep leukemic reservoir that is active in this patient. So I agree with the intent that we probably want to do something different. What that something different is up for debate right now. And I think all the points Eunice made are very valid, but I would be thinking about a transplant. And so, for that reason, would avoid additional gemtuzumab in a patient like this because you're going to transplant in soon proximity. Dr. Stone: So I think those are all great points. And I would just say that we don't even, this case tells us a lot more about what we don't understand about than what we do understand because first of all, it is possible to have one of the technologies (i.e., NGS positive or PCR positive) and have MRD flow negative or vice versa that was shown in the elegant paper a few years ago by the HOVON group, which showed that if you were positive by both modalities, it wasn't PCR for a fusion transcript, it was NGS for a mutation of diagnosis, which this patient didn't have. But anyway, if you were positive for both technologies, you had a very high relapse rate. If you were positive for neither technologies, you had a lower relapse rate, although some still relapsed. And if you were positive by one or the other, you had intermediate relapse rates. So there's a lot about the biology of these MRD cells that we do not understand. Why is that the case? Why is it the case that 30% of MRD-positive patients don't relapse? So it's not a slam dunk that this patient's going to have a clinical relapse down the road, though we're all concerned about that. So I think these are important points to make. Further, what we don't know is whether if we reduce the MRD, let's say we gave azacitidine/venetoclax, which is often done in a case like this because it does work in the relapse setting and maybe it'll work to get rid of this clone. You make the transplant doctors happier, but will we really have a better outcome for the patient? Because it already may be foretold that this patient is going to do poorly even after a transplant or not. So I think there's many questions that demand answering here. I think all of us would probably take this patient to an allogeneic stem cell transplant. Although I would always wonder in the back of my mind, if this patient was destined to do okay, and be in that good group, well, they wouldn't wait to find out. So I think this hopefully will be answered by studies that'll be done by the US Intergroup Group looking at the value of MRD erasure, but we really don't have a good MRD eraser yet. So the key clinical takeaways from this case is that the gold therapy in AML is to reduce the disease burden to the lowest level possible prior to stem cell transplant, assuming stem cell transplant is the goal, there were different techniques to measure MRD and they're complementary. And we know the presence of MRD prior to the stem cell transplant is bad. We don't yet know how best to approach it. And I think we can all agree that we don't know something when we don't know it. So in that vein, we now end our discussion of case four. But please see the other segments for further discussion about the latest data in AML or visit ascopost.com. Thank you very much.
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