DR STONE: So I saw a 54-year-old woman who presented with weakness, fatigue and shortness of breath. She presented to the Emergency Department. On presentation, she had a white count of 9,500/mcL with a hemoglobin of 6.6 g/dL and a platelet count of 17,000/mcL. Bone marrow biopsy confirmed acute myelomonocytic leukemia. Prior to the return of cytogenetic studies, she began induction chemotherapy with idarubicin and cytarabine. Her karyotype returned normal. Her AML FISH panel was normal. And PCR testing for FLT3, CEBPA and NPM1 and c-KIT were all negative.

The patient achieved a complete remission with induction chemotherapy. She did have an LP, which was negative. She subsequently received 4 cycles of consolidation chemotherapy with high-dose cytarabine. Following completion, or recovery from her fourth cycle of high-dose cytarabine, she had a repeat bone marrow biopsy that was normocellular with no evidence of leukemia. Her counts had completely recovered.

One month later, she became thrombocytopenic and a bone marrow biopsy demonstrated 10% blasts. Her complete cytogenetic profile was again negative. And she subsequently underwent induction chemotherapy with clofarabine/etoposide and cyclophosphamide. Her day-14 marrow after the start of that salvage chemotherapy was aplastic. And the plan is for her to undergo an allogeneic transplant, if she recovers in a complete remission.

DR LOVE: Lyle, maybe you can talk a little bit about the questions you’d like to see Jorge and Rich address.

DR STONE: So my first question is, what percentage do you quote to patients who have favorable-risk cytogenetics as to their chances of cure with standard induction chemotherapy?

DR CORTES: Yes. And here, we have to differentiate between the favorable cytogenetics, the translocation 8;21, inversion 16, and the intermediate risk, like the diploid patients. And if I heard you well, this patient was diploid cytogenetics.

DR STONE: And she was, in fact, intermediate, because she was —

DR CORTES: Yes, so in that category of patients, somewhere around 30% to 40% of the patients is what you can expect of durable remissions/cures, in intermediate-risk cytogenetics, yes.

DR STONE: Right. And in good risk, you typically quote…?

DR CORTES: Oh, in good risk you are up into the 60% to 70% probability of cure with a translocation 8;21, inversion 16s, especially younger — this is a 50-year-old. So these patients definitely have a probability of cure if they have good-risk cytogenetics.

DR LOVE: So I guess another question you had brought up, Lyle, was about in terms of testing patients up front. Maybe you can kind of verbalize that in terms of panel testing, et cetera.

DR FEINSTEIN: In terms of panel testing, other than what I described, specifically karyotype AML FISH panel and PCR testing for FLT3, CEBPA and PM1 and c-KIT, are there any other testing that you’re routinely doing in your center?

DR STONE: Sure. I think that’s a really critical point now. So you did the very standard workup for this lady, which was quite appropriate. I think what we’re going to see over the next few years is an expansion of the panel of genetic tests we’re going to be doing, because we, as Jorge said, IDH1 and IDH2 inhibitors are coming down the pike. They’re “not” clearly important in prognosis right now, except in more details we need to get into at the moment. But, knowing about the epigenetically active mutations like AXL1, DNMT3A, EZH2, it could be very important, because this lady technically has intermediate risk, but really, I bet that she had some of these mutations.

So to answer the question, and routinely what we do now, we do something called the rapid hem panel at Dana-Farber and Brigham where we send out on any diagnosed patient a 96-gene panel that covers all the mutations known to be driver mutations in AML. And we probably would have taken that patient to transplant in first remission, because her risk of relapsing is pretty high. Even if you look at the Schlenk paper in 2008 where they looked at people who were FLT3-negative and NPM1-negative, they did better with transplant than with consolidation chemotherapy.

DR LOVE: Before Jorge comments, for practical purposes for people in the community, I mean, could they send it to your place for the 96 gene, or what could they do?

DR STONE: There are many path labs that will do a much wider panel, Foundation Medicine being one.

DR LOVE: Do you recommend that?

DR STONE: I do, although I think, to be completely honest, the genetic tests that Lyle sent were perfectly appropriate. And a decision could have been made to transplant the patient on first remission on that basis. I think you would have seen other evidence — I’m betting. I don't know, obviously that this patient had other abnormalities that would have suggested a more deep problem in the bone marrow/stem cell than otherwise appreciated by that panel.

DR CORTES: Yes. I think that Rich brought a very important point. And the fact that we have some very basic molecular characterization that’s very critical to do on everybody, there’s a wider panel that’s important. Because even if we don’t have directed targeted therapies, for example, for a certain mutation, but if it gives you a good idea of better refining the prognosis of patients, then you can make a decision as to whether to transplant or not a patient in first remission.

The very broad panels end up finding a lot of things that have less clear implications. So I think that institutions like Dana-Farber and us, we end up having a broad panel, but not these huge panels of 400 genes. Because then you end up getting a lot of other pieces of information that you don’t know.

The only other thing that I would add to the workup that I think is gaining importance not so much at diagnosis but during the treatment is the measurement of minimal residual disease. We have the problem that it’s still not a very uniform method everywhere. And it’s evolving. So it’s not something that you can do easily anywhere and interpret it everywhere.

But the value of assessing minimal residual disease as patients receive treatment and respond, et cetera, is becoming more and more critical with or without a transplant. So I think that that’s something else that we’re going to be incorporating more and more into our treatment. We do it routinely, but it’s not widely available and it’s not uniformly done in every place.

DR LOVE: Rich, can you send peripheral blood for these assays, or you need marrow?

DR STONE: Yes. You can send peripheral blood if there are peripheral blasts. And sometimes even if there are not, because these diseases tend to be clonal. And you can get some information even without blasts in many patients.

DR COLE: So I do wonder if you want to do these bigger panels, does that require a second bone marrow on your patient, who may already be on induction by the time you’re getting things back and thinking, “Oh. Do I need to make a wider look?”

Sometimes I have patients who will go down to MD Anderson. They always get a second biopsy. They always get this big panel. A lot of things come back not supermeaningful to me. And the idea of FoundationOne testing in the community is somewhat difficult in getting it paid for. I have many patients with different types of cancers who get FoundationOne testing. And initially, they’re told, “Oh, if your insurance kicks it back, you will only have to pay $500,” but they’re still receiving bills for, like, $2,500. And this is a real thing that happens to my patients.

And so for me, it’s a little bit of a difficult thing to want to have this information that I may not be able to do anything about, because I’m in the community and I don’t have a clinical trial. And it may come back on the patient and cost them a lot of money.

DR LOVE: Jewel, I want to bring in your perspective and thoughts, particularly about this issue of working the patient up.

DR JOHL: Sure. I mean, I share many of the concerns Suzanne pointed out. The issue becomes, we order the standard ones you ordered, the NPM1, the FLT3, et cetera. So logistics are, which lab should we send these specimens to? Because hospitals have contracts with certain labs and not others, so sending a sample from the hospital becomes a challenge, because some of these patients are in the hospital for an entire month during induction.

And the other challenge, like you mentioned, is, how do you interpret some of these results? And what does it mean for me? Because what I want to know is, is this patient going to need a transplant or not? Are there any clinical trials, if I find a specific mutation? And that requires expertise of a specialist, like yourself.

And a lot of times when you refer patients to Stanford and UCSF, they run their own panel. So if you do a panel in house or send it to a lab, it’s going to end up getting repeated again anyways when they do go to an academic center, because they don’t trust anybody else’s lab. So that becomes a challenge, cost and logistics, like you pointed out. So some of the concerns are the same.

So we end up doing the routine, the FLT3 ITD and the IDH mutations and NPM1 and CEPBA. And we kind of leave it there and then leave it up to the academic centers to do the rest.

DR FEINSTEIN: And my question with respect to the molecular testing is the following: The NCCN has produced guidelines for the workup. And they include the standard 4 molecular tests. But now with these larger panels, as you had alluded to, IDH1/2, EZH2, what other molecular abnormalities would encourage you to send someone for transplant in first complete remission on these panels?

DR STONE: I think, just to answer that question and to follow up on some of your points, I don’t think you need to send a panel to an expensive lab. It’s not worth the money right now. It’s a great thing to be able to do.

But if you know the FLT3 ITD status and the NPM1 status and the C/EBP-alpha status in a patient with normal cytogenetics, you can make a good therapeutic decision. It can be backed up by the additional studies. So right now, I don’t think we — although we’d love to do it, I think we’re collecting data about the utility of these things. To make a transplant decision on someone with normal cytogenetics, you need to know those 3 tests.

And if they don’t have an FLT3 ITD mutation and they don’t have an NPM1 — there’s only 1 category in those. If they have a C/EBP-alpha mutation, they do well and they don’t need to be transplanted with normal cytogenetics. That’s pretty unusual. If you just look at FLT3 and NPM1, any combination other than NPM1 mutant, FLT3 wild type, in my opinion, gets a transplant in first remission. That’s what the data suggests, to put it in its most direct form.

So I think there’s a notion that normal-cytogenetics patients can do well with consolidation. I only think those with an NPM1 mutant, FLT3 wild type are in that category. Maybe you could argue that, if you have a low allelic burden, FLT3 ITD and an NPM1 mutation, you could get away without a transplant. But pretty much everybody else, in my opinion, gets transplanted. That’s my thought. And I think the NCCN Guidelines give you some wiggle room on that, but that’s my own opinion.

DR LOVE: Jorge, agree, disagree or in between?

DR CORTES: Agree for the most part. I do think that with a limited panel, you can make very strong decisions. And I do agree that there was a lot more controversy about the transplant in the diploid cytogenetic patients when we didn’t have all this molecular characterization. And certainly, some patients be cured with just chemotherapy. But as we’re starting to understand who are these patients, they end up being those patients that have the CBPA and the NPM1, without an FLT3, et cetera. So those are the patients who, for the most part, you can cure.

Now, because not everybody can get to a transplant, then what can you do? But if you can, those patients certainly, if they have FLT3, I agree. The data is evolving with the FLT3 inhibitors, et cetera. But as of today we still transplant those patients, even if we can give them one of these drugs.

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