Standard Approach to Treatment for Fit Patients with Newly Diagnosed AML

Dr. Naval G. Daver: So, then of course getting into the actual treatments and how all of these molecular cytogenetics will help us select these treatments, so we're going to talk about current and emerging frontline treatment options for acute myeloid leukemia. So, I'll start with what we call the patients who are suitable for intensive chemotherapy. I think, to just start with this word fitness, I'm not a big fan of because fitness usually means the patient's fitness who's sitting in front of you. But now we actually know that the biological fitness may actually be more impactful. So, if I have a 40-year-old who's healthy and very robust and fit, but he has a TP53 with a high VF or complex cytogenetics, I don't know if I really want to give intensive chemotherapy to that person. And the same with if I have a 71-year-old, a 72-year-old who has core binding factor or isolated NPM1 and my potential five year cure rate could be 80%, I may actually consider giving intensive chemotherapy. So, I think more and more the mutation cytogenetic or biological suitability of the disease is what many of us are using to determine treatment. Of course, there's always some component of fitness. We would not give an 80-year-old intensive chemotherapy and for younger patient who does not have clearly adverse-

Dr. Amir Fathi: You haven't been to Boston.

Dr. Naval G. Daver: You may not- I don't know what happens in Boston, but yeah. But I think more and more I think the underlying molecular cytogenetics is dovetailing into the decision making. So, what are the standard approaches for fit patients below 60? I think this is where we can really highlight the use of cytogenetic and molecular data. So, we check a FISH for PML-RAR APL. If we find that we're very happy, this is the best subset, not just of leukemia, maybe of all malignancies cure rates above 95%, chemotherapy free ATRA arsenic, that's great. Then we also check a FISH for inversion 16821. This is called a group of core binding factor AML. If we find this, this is where we add gemtuzumab to the induction regimen. And with this, we're seeing close to 80% or greater survival. We don't need transplant for majority of them. So, another good subset that we don't want to miss identifying. If you don't have those, then in parallel, of course, we're sending and waiting for molecular data. The big mutation that is going to change potentially your treatment is FLT3. So, if there's a FLT3 mutation, either ITD or TKD, then incorporating a FLT3 inhibitor. This was already established with a RATIFY phase three study midostaurin. But now there's also data with QuANTUM-First quizartinib that was published recently in the Lancet. And one can debate the different drugs, but it's great to have both the options. Quizartinib is very potent, second generation, drug targets ITD. And then the midostaurin does target ITD as well as TKD. So, we would definitely add a FLT3 inhibitor and consider allogeneic transplant. Just to highlight what Dr. Wang also said that it's very nice that- And actually because of the use of FLT3 inhibitors that we no longer use the ALLELIC burden co-occurring NPM1. If you have a FLT3, all of those are intermediate, use a FLT3 inhibitor to get those people a transplant. It simplifies the trajectory of treatment. And then I think the other one that we do look at, and others I know are also looking at frequently is TP53. So, if you have a TP53 in a younger patient- And with TP53, there is a little bit nuance. Usually, it's patients who have high allelic burden or associated adverse cytogenetics with TP53 that are the real TP53-driven disease. There's about 15, 20% that may just have a low TP53 VAF deployed cyto, we would probably give them intensive chemo. But for the majority, you have a high burden or adverse cyto, we really are moving away from intensive chemo. We would of course like to put a trial, if they have an option, CD47. APR will talk about those. But even if they don't have a trial, we are moving more towards the HMA-VEN based approach, try to get them to transplant without too much toxicity. So, I think that no longer is the frontline standard of care just anthracycline cytarabine for at least 45, 50%. We're doing something different, adding something or switching treatment. At MD Anderson, as many of you know, we are doing a trial where we are using a frontline more intensive regimen of FLAG IDA or CLIA-Venetoclax, which is showing very high responses. And early data looks like it may be improving survival. I think this has to be confirmed in randomized study, and those are being planned. So, that's kind of, I think the way we are looking at younger fit patients. But maybe here, just to kind of turn the question a little bit, and maybe I'll start with you Dr. Kasner, how do you view fitness? Is it similar to what I'm saying or do you look at different factors? What do you do for your patients?

Dr. Margaret T. Kasner: Well, I think that really the complication is that it is the disease that is making patients unfit. Or rather the question is, is it the disease that's making the patient unfit? So, for me, the assessment is what were they like a week ago, a month ago, six months ago? As opposed to a patient who may walk in with a breast cancer and whose performance status, which is what we are really talking about here is in- can be independent from their disease. But here, it really cannot be independent from patient's disease. If they come in with a hemoglobin of 5.5, I also would not be able to walk up the stairs.

Dr. Naval G. Daver: That's right.

Dr. Margaret T. Kasner: And so- and we see this all the time in the trials of patients who are deemed unfit for a transplant, and suddenly treating the disease makes them fit. And so, I think it is a more complicated question in AML than in some other diseases. And for me, it is really an assessment of who they were. But also organ function. So, if their EF is 20%, then no matter how functional they were before they got this disease, I mean, I can't give them the same kind of treatments or offer them potentially a transplant as I would otherwise. So, I do think, yes, it certainly comes into play, their performance status, but not just who they are today or a week ago while they have this acute leukemia. But rather trying to assess what their functional status was some reasonable distance in the past, a few months ago. And sometimes they really are that 72-year-old who was- noticed this when they were out on their 10-mile jog. And so even though they can't walk up the stairs today, that's OK because that's who they were a few months ago.

Dr. Naval G. Daver: And I think that's really important, the dynamic nature of what we use as fitness or performance data because we see this all the time. Even with the HMA-VEN where there were patients who were completely unfit, he's a 69-year-old with pneumonia, creatinine is 2.2, has some bilirubin, fatigued, hemoglobin is low. And you give this patient HMA-VEN or some lower intensity therapy, they go into remission, hemoglobin is good, pneumonia is gone, creatinine normalizes, and that patient will go to transplant. And people say, well, but you said he's unfit, and how can he go to transplant? But we do see this.

Dr. Margaret T. Kasner: Doing our best:

Dr. Naval G. Daver: So, I think that one should not make a decision that is going to be pervasive throughout the course of treatment. I think it's a fitness at that point, you choose the best treatment at that point, and then you reassess. And maybe that could be turned into a curative option.