DR CORTES: So this is a patient that’s one of those healthy, physically active patients and 67 but no major comorbidities, et cetera, has a trisomy 8 and a diagnosis and then IDH1 mutation. We talked about how these 2 things not infrequently come together. So the patient receives induction chemotherapy with fludarabine and cytarabine, so like a FLAG regimen.

Now he’s in remission, and he has minimal residual disease detectable at low levels, 0.08. And the thresholds here are difficult to interpret, because, as we talked already, there’s no standardization, et cetera. But it is detectable — low but detectable. And so this brings the issues of how you consolidate a patient like this, things like high-dose cytarabine, considering transplant, incorporating an IDH inhibitor.

And now they’re in clinical trials, but let’s think about also the future, et cetera, and the value of the minimal residual disease, how you incorporate that into your decision-making and all of these aspects. So I’d like to see what Rich would think about a patient like this.

DR STONE: If the mutation panel now still shows an IDH mutation and I had my druthers — and I wouldn’t be able to do that now — I would give an IDH inhibitor, get him to a negative MRD state if that works and then maybe transplant him.

Right now you’re faced with the choice of transplant now or additional therapy. Realistically, he’s going to get some additional therapy, because his donor may not be identified right away. So I probably would give him modified high-dose ara-C while I’m waiting to transplant him.

DR LOVE: When do you use, Jorge, FLAG as opposed to 7 + 3?

DR CORTES: In our institution we don’t use 7 + 3 ever. We use higher doses of ara-C, so like a 1 to 1.5 grams/m² for 4 days and 3 days of an anthracycline, typically idarubicin. That’s our standard therapy.

DR STONE: Are you going to modify that patient, the results of the trial led by Dr Garcia-Manero?

DR CORTES: The SWOG?

DR STONE: The SWOG trial, which showed that that was inferior to 3 + 7.

DR CORTES: We should.

DR STONE: Yes.

DR LOVE: Can you elaborate on that?

DR STONE: Sure. So there was a very large Southwest Oncology Group-led trial. The PI was our friend Guillermo Garcia-Manero, who’s at MD Anderson. It was a randomization between 3 + 7, IA, which is the MD Anderson-intensified induction that Jorge just mentioned, or IA plus a histone deacetylase inhibitor called vorinostat. The vorinostat arm dropped out early, because it was inferior.

So then at the end of the day, it was MD Anderson induction versus standard induction. And I believe that we’ll hear more about this, but it looks like IA was not superior, especially in people with favorable chromosomes. So that’s why I asked him that question.

DR CORTES: Yes. I mean, we’ll have to see the final results. The addition of the vorinostat, which, interestingly enough, was the initial intent of this study, that arm was closed and it was determined that it was not effective. And it’s even more toxic, et cetera, so that drug died. The readout of that is out.

But then as the study was being designed, this is not the standard chemotherapy. The standard is 3 + 7, so we’re going to need a third arm where we determine whether these — because this was IA plus/minus vorinostat, but is IA as good or better or worse than 3 + 7? So a third arm was added from the beginning at the design. This was the discussions when this was being designed, to say, “Let’s have a 3 + 7.”

So the interesting thing will be to see the final data of this 3 + 7 versus the IA and see if indeed the IA is any better or any worse than 3 + 7 and whether 3 + 7 could sadly remain the standard. And I say “sadly” because it’s not a very effective therapy, although with all the iterations of modifications that we’ve attempted through the years, we still haven’t been able to get anything better than that.

DR STONE: And the IA versus 3 + 7, it hasn’t really been presented. So I’m just hypothetically asking, really. We’ll know at ASH.

DR CORTES: So the question is, if it comes lower than 3 + 7, should we change our strategy at MD Anderson that is not as good as 3 + 7 or even if it’s equivalent? Because if it’s equivalent, you could argue, “Then what’s the point of doing this higher intensity?” And the answer would be that, “Yes, we would need to reassess our strategy if that’s the case,” because now, obviously, adding other drugs to this 2-drug combination in whatever format has not been useful for the most part.

But the other thing is that what we’ve added to these other drugs has historically been another chemotherapy drug — etoposide and this and that. When you add any of the newer drugs, you add midostaurin for a specifically defined subset of patients, then you start getting benefit. So I think that this strategy will be that, adding other drugs but other drugs that make sense in some way rather than just another chemotherapy drug that probably you get as much as you can get with this 2-drug combination.

DR LOVE: So just to clarify, it sounds like you’ve had an early confidential look? Or you’re just guessing?

DR STONE: I’m just guessing.

DR LOVE: Just guessing. Interesting. Okay. I always like that. What would your guess be, incidentally? What do you think the trial’s going to show?

DR CORTES: I’m certainly biased for the IA, so I am hoping that the IA will be better, but it would not be the first time I’m wrong.

DR STONE: But we will know at ASH. I think it’ll be presented.

DR COLE: Biased, because it’s easier on the patient? It’s easier?

DR CORTES: Yes, we’ll soon see. I’m sorry?

DR COLE: Is it easier for them to get through the IA?

DR CORTES: No. The 3 + 7 is easier. It’s less myelosuppressive. It’s a lot easier, the 3 + 7. This is a little bit more intensive, the IA. That’s why I’m saying, if it turns out that it’s even equivalent, does it make sense if you’re getting a little bit more myelosuppression, which means more neutropenic fevers and all these things? Of course if it’s inferior, but even if it’s equivalent, does it make any sense?

DR STONE: And, actually, in the consolidation it’s less intensive. So there was some concern about giving that to favorable-cytogenetics patients.

DR CORTES: And that is true.

DR STONE: We’ll have to wait and see what happens.

DR CORTES: Yes, although in the favorable we do something different.

DR JOHL: The issue is, even if it’s a positive study or equivalent outcome, the patients at MD Anderson are highly selected patients. In the community, we don’t see those highly selected patients. What we’re going to see are 60- and 70-year-olds who have other comorbidities. So sometimes it’s hard to translate the MD Anderson data into the community practice.

DR STONE: Although this trial was done in a community.

DR JOHL: This was done in the community?

DR CORTES: This is the community. And I would somewhat disagree a little bit with this. It’s not that our patients are that much different. I mean, keep in mind we’re a state institution and we do treat a lot of patients that are — everybody that’s, like, in the community there locally, they come to MD Anderson. Like, the county hospitals, they treat the solid tumors but not the acute leukemias. They come to us.

But the setting is different. And you have to be realistic with your setting. We can give treatment Saturdays and Sundays. I have a blood bank that has almost unlimited resources. I have coverage day and night. My setting is different than your setting even if the patient is the same.

And you obviously have to be cognizant to do something that is doable in your setting. Extrapolating something that’s doable in this setting is not what you should do. My former colleague, Sergio Giralt, who’s from Venezuela, so we frequently ended up in tours giving talks in Latin America, he uses the term to “tropicalize the transplant.” And what he meant is, you’re not meant to replicate what we do at MD Anderson — you’re meant to take those things and adapt them to your medium. I mean, sometimes that means some variation of that.

I worked in Mexico, and I was doing the hyper-CVAD. But I had to adapt it to what I could do in the setting where I was working at MD Anderson. So it was a modified hyper-CVAD. So we need to be cognizant.

DR STONE: Let me ask you this: I mean, this is a controversial topic, which you must bring up. Should all leukemics under a certain age be referred to a tertiary care center for treatment? There are tertiary care oncologists who make that statement day in-day out, as you’re probably aware.

DR CORTES: Yes. And I think that, ideally, yes, if it’s a patient who’s going to be molecularly characterized and transplanted and all these things that someone is going to be having.

DR STONE: But how do you know what to start?

DR CORTES: However, the reality is that you cannot do that, because of insurance, because of preference of the patient, because of many factors. So I think that we should not fight that battle, because it’s not reality. What we need to do is make sure that the patient who can get to that setting goes and the patient who cannot gets the best treatment possible locally. And that’s why it’s important to recognize all the factors that we’re doing here, because the overwhelm — I don't know if a majority or a significant percentage or whatever, but even if everybody agreed with that notion, it’s not going to happen.

DR STONE: I totally agree.

DR LOVE: Suzanne, any thoughts having come from MD Anderson?

DR COLE: So I think that it’s important to recognize that not everyone has that option to go somewhere else. I also think it’s important that our great institutions should be training oncologists that are going to go back into their communities and serve their population with excellent training, good connections, having insight and experience of — I think that it would be very different for me to even be able to do acute leukemia in the community had I not had exposure to hundreds and hundreds of patients and gotten my feet under me and felt confident that I could actually take care of these patients in the community. And I find it is a great source of pride that I’m able to offer this service to people who may otherwise die because they don’t have the option to go somewhere else.

[The results of the SWOG-S1203 trial presented at ASH 2016 indicated no difference in event-free, relapse-free or overall survival between the 3 treatment arms for any standard-risk subset. Patients with favorable cytogenetics had significantly better event-free, relapse-free and overall survival with 7 + 3 therapy compared to idarubicin and high-dose ara-C or idarubicin and high-dose ara-C with vorinostat.]

Module 1: Current and future approaches to targeted therapy for acute myeloid leukemia (AML)

Module 2: Other clinical issues in AML management

Module 3: Case discussions