Acute Myeloid Leukemia Podcast

Intermediate-Risk Acute Myeloid Leukemia

Gail J. Roboz, MD; Pinkal Desai, MD, MPH


May 19, 2022

This transcript has been edited for clarity.

Gail J. Roboz, MD: Hi, everyone. My name is Dr Gail Roboz. I'm a professor of medicine and director of the leukemia program at Weill Cornell Medicine and the NewYork-Presbyterian Hospital in New York City. It is my great pleasure to welcome my friend, colleague, and close collaborator, also from Weill Cornell Medicine, Dr Pinkal Desai. Pinkal, thank you so much for joining today.

Pinkal Desai, MD, MPH: It is my absolute pleasure.

Roboz: Today we're going to talk about intermediate-risk acute myeloid leukemia (AML). AML is a difficult disease, and it basically comes in three flavors: good, bad, and medium, or favorable, intermediate, and adverse risk. This is a gross oversimplification, but the truth is that intermediate-risk disease really includes the majority of AML patients. I think it's very, very important for the audience to understand the classification of AML patients because this is what really drives not only the prognosis but also therapeutic decision-making. Pinkal, what do we mean by intermediate risk, what classification should we be using, and who's included in that category?

Desai: Two things come up. One is the European LeukemiaNet (ELN) intermediate risk, which basically takes into account both the cytogenetics and the molecular mutations. And there is also the cytogenetic intermediate risk. When we're looking at trials, it's important to understand which category of patients went into these trials. Was it intermediate ELN risk or was it intermediate cytogenetic risk? Because if you look at the cytogenetic risk, the biggest category here is normal cytogenetics, which is the single largest cytogenetic abnormal abnormality that falls in AML and in intermediate risk itself. In addition, trisomy 8 and 9;11 translocation also fall into the cytogenetic intermediate-risk category. Now, if you look at the ELN risk, which takes into account the molecular sort of abnormalities in addition to it, then the biggest categories that are included in this intermediate risk is mutated NPM1 with a FLT3-ITD high allelic ratio. High allelic ratio, as you know, is 0.5 or more than 0.5. So having a mutated NPM1, FLT3-ITD high is considered intermediate with obviously normal cytogenetics. The other category would be a wild-type NPM1 mutation without any FLT3-ITD, or FLT3-ITD low allelic ratio, which is less than 0.5. Those are the molecular groups that go into it. ELN intermediate also includes, in addition to these two that I discussed, the 9;11 translocation and any other cytogenetic abnormalities that don't fall into the good and the adverse risk. So it's kind of like that mixed-bag category.

Roboz: I think you made a terrific point that not all intermediate risk is exactly the same because there are plenty of clinical trials that were conducted prior to having molecular genetic information that is now standardly available for AML patients. But lots of clinical trials didn't include that information, and they may have only had intermediate risk assigned by cytogenetics. So it underscores the point that when you're looking at clinical trial data, actually look at which patients were included and make sure that the ELN classification vs, for example, an old standard that was termed, let's say, CALGB classification or other cytogenetic-only classifications, might have been used. ELN stands for European LeukemiaNet, so that is commonly used throughout the world, not only in Europe. And obviously, the combination of molecular and cytogenetic data is critical in AML. But there, too, it gets complicated because you used a lot of terms that may not be familiar to somebody who doesn't think about AML all day long. So I want to unpack those within some of the mutational subcategories of AML — for example, the NMP1 or nucleophosmin mutation is a common one, and it is one that people look at and they say, "Oh, you have an NPM1 mutation — that's good. It's in the favorable risk category." However, I think it's important to be specific and ask, "Who are the friends of NPM1 or the enemies that are hanging out with it?" For example, if you have a mutation in NPM1 and a FLT3 and ITD mutation. Again, FLT3 also comes in two flavors: ITD and TKD with a high allele ratio. I would imagine that people listening to us might say, "Hey, what is that?" What are we even talking about? We don't even get back an allele ratio in our report. So can you talk for a minute about when you get back that FLT3, how should people take a look if they're getting a PCR result back or if they're getting a sequencing result back? And how do I even know if I have the high-allele ratio? How do we unpack that?

Desai: The PCR would be able to tell you the ratio of what is wild-type vs what is mutated. And usually there is this magic cut-off that has been established, of 0.5. If it is equal to 0.5 or above, it's considered high, as in that this is a high allele burden of FLT3, which might drive aggressiveness of leukemia. These are associated many times with very high white cell count and poor outcomes. So that's to be treated as a different category. So, when you have a good mutation like NPM1 and then it's associated with the FLT3 high, it kind of drags the goodness of NPM1 into the intermediate category from being sort of good, and anything that is under 0.5 is not considered high. But if you have that as a single without an NPM1, that is also intermediate risk. So if you have no NPM1 and a low FLT3-ITD, that's also considered intermediate. Now, when you have sequencing come back, that usually takes about 2 weeks. You can also get these results, but they are mostly point mutations that can tell you which kind of TKD mutation, which is another kind of FLT3 mutation — tyrosine kinase domain mutations. But it's not the best in giving you the allele ratio, which a PCR does better and faster.

Roboz: NPM1 by itself is one thing, but NPM1 may not necessarily be a favorable risk type of a patient. FLT3 actually may not necessarily be an adverse-risk patient. I think that's the point to drive home, that again, not to try to oversimplify the data. I can also say that in different institutions, people actually are less attached sometimes to the allelic ratio, and people will just make an institutional or a programmatic decision that if you have a FLT3-ITD irrespective of the allele burden, some institutions will treat that as an adverse risk. There too, it's important to think about the total treatment that you have planned for the patient and how overall that's going to move into your thinking. People also sometimes get, I think, bogged down in having a look at what the allele burden is with respect to whether they apply a FLT3 inhibitor. And there, too, I would say that there is some controversy in the field that sometimes people will look and say there's a very low-burden FLT3. They may or may not apply a FLT3 inhibitor out of the gate. But that said, let's go into some standard management decisions. So for a standard garden variety 40-year-old who walks in in good shape, who has a normal karyotype, doesn't have a FLT3 mutation, what is going to be the standard treatment paradigm outside of clinical trials, which is always the right answer for every AML patient? But what's going to happen to a patient who walks in with intermediate-risk disease, and initially without a FLT3 mutation?

Desai: For somebody who doesn't have FLT3 mutation and is young, has no comorbidities that don't allow any intensive chemotherapy, the standard of care is basically an anthracycline and cytarabine–based induction chemotherapy, which is the most standard used — 7+3, as people call it, whether it is with idarubicin or daunorubicin. There are institutional preferences to it, but the idea is some kind of backbone of 7+3 is considered standard of care. The other possible addition to this backbone is gemtuzumab ozogamicin (GO), which is a CD33-linked chemotherapy calicheamicin that is also approved for intermediate-risk AML based on disease-free survival advantage for these patients. It is not always standard to add the gemtuzumab, or GO arm, to the 7+3. Many institutions have adopted that, and some have not because of the way the data were when they came out — that addition of GO was obviously very helpful for favorable, and for intermediate, there was some benefit.

Roboz: I think the 7+3 regimen is actually older than both of us. That has been around for a very long time and we still use it a lot. We don't seem to have fully settled in the past 50 years of exactly how to give it, but a standard anthracycline and cytarabine–based backbone is going to be what's typically used for intermediate risk. I think if you have a FLT3 mutation, it's standard to add a FLT3 inhibitor. And certainly for anybody with FLT3 mutations, I would say again, off of a clinical trial, it would be standard based on the RATIFY clinical trial to add, for example, midostaurin to 7+3. The application of different FLT3 inhibitors — there are emerging data, but even for intermediate-risk patients, I think if you have a FLT3 mutation, you're probably going to get a FLT3 inhibitor. The application of GO, as you pointed out — I want to highlight that there is a very uncontroversial benefit for the good-risk patients for the core binding factor patients. And I would say the majority of institutions have adopted the addition of GO as standard for those patients. But I agree with you that it's a bit more controversial in the intermediate-risk group and different institutions have different policies about this.

That said, there was an event-free survival benefit in the low-dose fractionated schedule of GO when adding it on to a 7+3 backbone. Now, there's some controversy there, and I'm curious how you feel about this. I mean, I think that the data have been pretty clear over the years that there is a strong push to go to an allogeneic stem cell transplant as the post-remission therapy for the intermediate-risk group, based on a lot of data suggesting that, for eligible patients with intermediate-risk disease, the overall survival is better with allogeneic transplant than with standard types of consolidation chemo. And I think people do worry about the small but not zero risk of VOD or, veno-occlusive disease, otherwise known as SOS, sinusoidal occlusion syndrome, with gemtuzumab. Maybe they're thinking, Well, if I might send this patient on to a transplant, am I worrying about the addition of GO, even though it has been shown that you certainly can transplant those patients? But how do you feel, first of all, about the post-remission therapy for intermediate risk? And second, does that change your thinking at all in applying the GO upfront? Is that part of the calculus at all?

Desai: Most intermediate-risk patients are transplanted, and as you pointed out early on, intermediate is not normal and intermediate doesn't mean that survival is actually great. So you do want to do your best to cure the patient, and that does include a stem cell transplant. There are some people who may not be eligible, or on a case-by-case basis, you may decide that this person might be okay without a transplant. But overall I think we do transplant and the worry about GO is there. There's also how many doses of GO is good enough, or can you give one dose and that's safe enough prior to transplant vs a more intensive GO dose? But you do think about that because currently we don't have good therapy for VOD disease post-transplant. It’s almost a death nail once that happens. If we know that somebody is definitely going to get transplanted, you kind of think about that. On the other hand, just to play the devil's advocate, why does GO have better event-free survival than the CR rates or complete remission rates are kind of equivalent? And it's possible that it's because of deeper measurable residual disease (MRD), so is it better to get into a deeper MRD and then go to transplant and hence improve transplant outcomes? And how does that actually put up against this risk of a VOD? That's just to play the devil's advocate. That is also something you do think about: Am I better off with or without it?

Roboz: I think we do know that there are mitigation strategies that have been discussed and published. If you have somebody who has known liver disease at the outset or has known risk factors because of prior chemotherapy exposure or something that would increase the risk for VOD, that's one thing; but in another, there are patients who don't have those risks. I definitely think that your point is well taken. It's difficult to prove because they didn't have the data from the clinical trial. But certainly something is driving that event-free survival benefit, and I think many people are suspicious as to whether or not that could be a deeper remission, that they just didn't have enough data to support. So I think it's worthwhile to consider, and I do think that many institutions have in fact adopted GO in the low-dose fractionated schedule for intermediate-risk patients. Now, one of the things I just want to touch on for a second is the 9;11's or the KMT2A patients who are included in the intermediate risk. Those patients are going to be, for right now, treated kind of similarly to what we're describing, but I think it's worth mentioning that one of the hot topics right now in AML — this is not restricted to intermediate-risk patients in the newly diagnosed setting that we're talking about — is Menin inhibitors. They're a class of drug to watch and are currently being investigated in patients with relapsed disease who have 9;11 or KMT2A abnormalities, as well as NPM1 patients (NCT04067336, NCT04811560, NCT05153330, NCT04988555). I just thought I would get that in there as something to watch. But I want to get back to transplant for a minute because we all transplant all of our intermediate-risk patients. But do we actually do that? I mean, I feel like we have the same program together, certainly have seen patients who, for one reason or another — and they're not necessarily 99 years old — might not be able to go on to a stem cell transplant. So does that feel like a reality?

Desai: I would say yes. The reality is that not every intermediate-risk patient goes to transplant (either patient preference or just had a hard time during induction), and patients don't want to then go through transplant for several reasons, patient driven and physician driven. In those patients, you obviously do need post-remission therapy, and the standard post-remission therapy then would be cytarabine based consolidation. The exact number is unclear; depending on the age, you want to give at least two and possibly up to four cycles of cytarabine-based consolidation, depending on how the patients do during consolidation. But that's the alternate post-remission therapy for consolidation. And there's more stuff you can do after chemotherapy as well.

Roboz: One recent dataset that we have discussed is coming from a trial called QUAZAR, which actually started accruing a long time ago when the eligibility for the trial was exactly to one of your earlier points — that it was based on intermediate-risk cytogenetics. So those patients got treated with intensive chemotherapy. Something happened and they weren't eligible for stem cell transplant. They got some level of consolidation therapy, depending on the investigator’s choice. And then they ended up getting oral azacitidine maintenance. The QUAZAR data showed a survival benefit for oral azacitidine maintenance for those patients. It's not saying that it was better than transplant. Those patients couldn't get transplanted. But I would say that, to your point, when you give chemo, you wanted to do a transplant, you couldn't do a transplant — you do some consolidation if you can, and then you can put those patients on to oral azacitidine.

Desai: I think you made the point well, that you start with the intention to transplant and when that does not go through, the alternative is consolidation, followed by oral azacitidine maintenance. But at least at this point until we have better data, it is not considered an equivalent. The way the trials enrolled, the intention was to treat only the people who are not eligible for transplant. And that's how we are triaging our patients too.

Roboz: These days, things are looking better for patients who are in all AML categories who can't get intensive chemotherapy. But what are we giving for an intermediate-risk patient who's 78 years old or who's 80 years old or who's even younger than that and not getting intensive chemotherapy? What's the new standard of care?

Desai: The old standard used to be potentially low-dose AraC or hypomethylating agents (HMAs). Now with the VIALE-A trial, we have data that showed that HMAs in combination with venetoclax had a survival advantage over a single-agent HMA therapy. So that would be one standard of care. For complete remission rates, we used to never get it over 30%-40%, and now it's approaching the complete remission rate of what we were achieving with intensive chemotherapy, which we obviously cannot give to these older patients with leukemia. So I would say that ongoing continuous cycles of HMA plus venetoclax is an option. Now, HMAs may not be available in every country as a standard or difficult to get. Low-dose AraC is also a valid backbone. The phase 3 trial of low-dose AraC plus venetoclax compared to low-dose AraC did not meet survival endpoint, but there were several reasons for that. These were heavily HMA-treated patients that went to it. If you just look at the people who didn't have HMA, actually low-dose AraC plus venetoclax was not any different, but that would be an option for patients where HMA is not available or you can get it in certain countries. The other regimen that is also approved in this situation is a hedgehog inhibitor with a low-dose AraC backbone, which is also in theory approved and could be used in these patients.

Roboz: We're doing much better than we were. So you have intermediate-risk patients who now have the ability to have improved rates of CR, as well as overall survival, with the addition of venetoclax to an HMA backbone. Those patients were typically not getting anywhere near the remission rates of 60%+ that are seen currently, and they certainly were not getting past that 6- to 9-month survival and are now doing better. I would say there are also a handful of patients who start out with an HMA/venetoclax-based regimen who can ultimately go on to transplant, and I think those are really emerging data in the intermediate-risk space of how could an HMA-based induction actually allow more patients to go on ultimately successfully to allo-transplant? So I think that rounds out a very good discussion of intermediate-risk AML. Pinkal, I really want to thank you again for joining me in the discussion, and thanks so much to the audience for listening.


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