Optimizing Treatment Selection for Patients with FLT3-ITD AML

Dr. Naval G. Daver: So, let me open it up. I mean, obviously, a lot of choice, which is great compared to 10 years ago where we were all a bit depressed and just having to decide the dose of the anthracycline and how to modulate the cytarabine. Now, we actually have a better discussion about what targeted therapy and where to use it. So, let me ask Dr. Fathi and then Dr. Kasner. So, QuANTUM-First, positive, published Lancet data looks good. Quizartinib, yes, I think is tolerability wise a little bit better in my opinion. But what is your approach? Let's say quizartinib gets approved, we hope it will in the next few months. You see a new FLT3 50-year-old patient in your clinic, ITD mutated. What's your process going to- thought process in that patient?

Dr. Amir Fathi: My thought process is always agree with Eunice, that's my though process.

Dr. Naval G. Daver: There we go, easy answer.

Dr. Amir Fathi: Thought process two is right now the quizartinib is not approved, so the choice for that patient who is sure functionally fit is obviously seven and three in midostaurin. I do agree that midostaurin is tough, man. I mean, lots of GI toxicity, lots of nausea, liver enzymes are an issue. So, it is difficult. I probably compared to some of the other folks on this panel have less experience with Quizartinib. And when that- in general, when that happens with these drugs, I'm very eager to start using them, so I gain experience. Because the data that's emerging and has been recently published is very promising in my opinion. And quizartinib is cleaner, it is very potent, more so than midostaurin, and selective. And for an ITD patient, maybe more suitable and maybe something that they can continue to take without constant challenges. Now, one of the things that came up briefly here is much of the success around FLT3 inhibitors is in my view, at least, the duration and longevity of treatment. And in order to have success with these drugs, you need patients to take them. So, if you have drugs that are better tolerated over time and patients can take them and won't have issues with them, I think the chances of longer term success are higher. Of course, we don't have necessarily data to demonstrate quiz versus midostaurin versus gilteritinib quite yet, but we may in time.

Dr. Eunice S. Wang: So, I have a question. So, one of the major- So, would the age of the patient matter? Here this patient is 50 something, but they're 70 some, 71. So, the RATIFY data was only up to 59. So, if the patient was 71, would you prefer more quiz data, be quiz, or did that not make a difference?

Dr. Amir Fathi: It depends how hardcore you are about the rigorous of the data. I'm not that hardcore. So, I actually rely on- I shouldn't probably have said that. But I rely on the biology-

Dr. Naval G. Daver: You're very hard- you're hardcore, Amir's hardcore. We'll get him back to hardcore.

Dr. Amir Fathi: I rely, and I'm sure- I suspect some of you do as well, we rely more on more these days on the biology. So, choosing, for example, a FLT3 inhibitor or maybe CPX versus traditional seven and three. I think most of us would look at a 70-year old who is robust and fit and not worry as much whether they are 60 something or 72.

Dr. Eunice S. Wang: But what about the cardiac toxicity? The one thing with crizotinib is it does have that side effect of the QTC prolonging data.

Dr. Naval G. Daver. So, I'll make a- So, a couple of- One is there is data that they didn't show, and I think that's why people aren't very familiar. But it's in the paper, in the supplement is the age cutoff, so below 60 and 61 to 75. Actually, when you look at that data, I personally am actually very less excited to give anybody intensive chemo FLT3 because the 61 to 75, the median survival is around 14 months. It's not impressive. And the early drop off is very steep, almost 25% die within that first two and a half month-

Dr. Eunice S. Wang: Because of toxicities?

Dr. Naval G. Daver: Just intensive chemo. I think it's just showing, again, that intensive chemo in the older AML population is a tough sell. Even in academic centers, in a clinical trial controlled setting, the early mortality is not that different from a decade ago. It's about 25%, 60 to 80-day mortality. So, I really think that if I had this older patient population, and we'll get into discussion whether you do azifine, you do azifine, gilt, do you sequence them, do you combine them? But I personally am really away from intensive chemo in that population. The other point I think that's very important is that the one thing I really like about the quiz is that when you look at the survival in patients who go to transplant, everybody benefits. With RATIFY, the survival was great. With quiz, the survival is great. But the thing that we saw with quiz that was not seen with the mido was that even in those who don't go to transplant, because the reality is even in ultra-large academic centers, the best we can do is 60, maybe 70% go to transplant. There are always hurdles, logistics, finances, patient choice, donor. But there, quiz showed a benefit in survival in that subset, which was not seen with the midostaurin.

Dr. Eunice S. Wang: That's because the duration.

Dr. Naval G. Daver: That is because of the duration is-

Dr. Margaret T. Kasner: So, that's going to- What I'm really interested in seeing is does the FDA say, as opposed to with midostaurin, we are approving this as kind of a package deal, upfront consolidation maintenance. Because if you pull the data apart, it's not clear-

Dr. Naval G. Daver: I agree with you-

Dr. Margaret T. Kasner: -how long they really need. But in the non-transplant patients, they do better.

Dr. Naval G. Daver: They do better.

Dr. Margaret T. Kasner: So, they need it- They need it for some duration of time that maybe we can't tell from the quiz. The allo patients, it's not as clear because maybe what they got was enough. Maybe they've got enough FLT3 inhibition plus an allo, and they're all set. But those other patients- And so I'm curious- But I think it will be approved that way, package deal.

Dr. Amir Fathi: Just-

Dr. Naval G. Daver: Go ahead.

Dr. Amir Fathi: A couple of comments. I don't pretend to know something I don't. I mean, I think in general when you look at data, and again, it's hard to look at subsets. And I think in general the survival advantage applied to the group as a whole. And obviously, if we divide them, we may see differences. The other thing I would say is we don't really know the true advantage or disadvantage of midostaurin because many of these patients that we've treated with midostaurin in recent years, I've ended up getting post-transplant maintenance. They end up getting gilteritinib-

Dr. Eunice S. Wang: With gilteritinib. Where I think that data's coming out, I mean, that data-

Dr. Naval G. Daver: We'll get to that, that EHA.

Dr. Amir Fathi: So, EHA. So I think- I agree completely, I think much of the advance and revolution in terms of the therapy of these patients with FLT3 mutations who used to be so ugly- not the patients, the disease- in terms of how people did, it's due to post-transplant maintenance therapy. I mean, I think it's-

Dr. Eunice S. Wang: Well, I think that's part of a whole package. If you are- if you have a FLT3 inhibitor and you can- If a patient's FLT3 mutant, you should add it to every stage of their treatment, the induction through maintenance, if they go to transplant what is your rationale not to do it, is potentially if we have, you know, MRD, that shows us that it's not there anymore.