Acute Myeloid Leukemia: Evolving Through Targeted Therapies - Episode 2

FLT3-Mutated AML: Early Aggressive Therapy vs Transplant

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Harry Paul Erba, MD, PhD: Let me ask a question of Amir about this allelic ratio and how it impacts further discussion. Amir, are there patients who have such a low allelic burden of FLT3 and maybe other mutations where allotransplants should not be recommended?

Amir Fathi, MD: If you ask multiple leukemia doctors you’re going to get a series of potentially different answers. Having trained with Mark, I have learned to have a very healthy fear of FLT3 disease, specifically FLT3 ITD disease. It tends to relapse; it tends to come back very quickly. Relapsed disease is oftentimes difficult to overcome, although we do have much better targeted drugs right now to manage them.

I tend to be more aggressive when I see FLT3 ITD disease—I recommend midostaurin with induction chemotherapy followed by transplantation. Thereafter, institutionally we recommend post-transplant maintenance therapy. And Mark Levis and a colleague of mine at Mass General Hospital have led a very large phase 3 study, which we hope to have results from in the fairly near future, to let us know ultimately if a very effective potent selective FLT3 inhibitor is going to be helpful in that regard. So I have a healthy fear of it. I recommend aggressive therapy, and I recommend a good amount of FLT3 inhibitor therapy spread throughout the course of treatment.

Mark J. Levis, MD, PhD: Looking more closely into the methodologies of transplant, which is what I’ve been spending my time doing, not all transplants are the same, and not all transplants offer the same low toxicity. The donor matters, the prep matters, and the circumstance matters. Harry’s point is a good one. Low allelic ratio, NPM1, no DNMT3 present, particularly if all I have is 6 of 10 Labrador retrievers as the best donor. But there are donor combinations that are kind of like that: female into male. It’s not a surgeon question. Every patient needs to be examined carefully for a decision like that. Of course, you know we’re all about transplant here. In fact, it’s a good point to reflect on.

Gail J. Roboz, MD: I was just going to react to something Mark also brought up that I think is really important. You know, we’re looking for ways to simplify things that aren’t simple. For people who aren’t who aren’t living and breathing AML [acute myeloid leukemia] every minute, you’re like, “OK, I see FLT3 mutation. I’ve got to hit that with a FLT3 inhibitor.” But if I see an NPM1, then I don’t have to worry so much. But wait a minute, what if there are 4 other mutations, plus or minus the DNMT3? I think it’s worse. The point is not to just buy into any reductionist view of this. We can’t just say, “FLT3 transplant, NPM1 don’t transplant.”

There are too many other factors, whether it’s concomitant mutations, allele burden, or donor type. It’s really complicated, and the take-home message is that all the separation into mutational subcategories, the availability of targeted inhibitors, doesn’t actually make for a simple bingo game. Some of these patients really are being told, “If you have this, you’ve got to do that. If you have this, you’ve got to do that.” Actually, there’s a more complex total picture that needs to be looked at. Not to mention that if you look at subtypes—for example of DNMT3A mutations—that’s complicated. It’s complicated to read the report. “Is this the bad one? Which one is it?” It’s a lot to ask if AML isn’t front and center on your daily routine.

Harry Paul Erba, MD, PhD: I agree with all those comments. I have patients in my clinic who have had low allelic burden set 3, nucleophosmin, no DNA methyltransferase 3A. The long-term survivors after consolidation are typically older patients in that group.

For our viewers the data that the faculty have been really alluding to is the paper in the New England Journal of Medicine by Elli Papaemmanuil, PhD, et al. showing that the biggest impact of the FLT3 ITD mutation are in patients with nucleophosmin and DNA methyltransferase 3A mutations. But Gail’s point about the different mutations is well taken.

Mark J. Levis, MD, PhD: And the ELN classification is another interesting point. I like it and hate it. It really consists of lumpers. It crammed an inversion 16. Basically a 22-year-old with inversion 16 and no other mutations is the same as a 69-year-old with a FLT3 ITD, 40% allelic ratio, NPM1 mutated.

And in fact their own data says no, it’s not, those do separate out. So the ELN is not something to say, “This is how I treat.” It gives you a good prognostic information. I love it, it really does hold up, but there’s so much more to understanding it.

Harry Paul Erba, MD, PhD: This has been a very interesting discussion about the prognostic significance of this mutation and many others. But let me wrap this up into maybe 1 concluding statement.

It is incredibly complicated how all these mutations are interacting in determining the prognosis of patients. On top of that you layer what your patients are able to tolerate in terms of therapy. And because of the uncertainty of all this mutational analysis and how it impacts prognosis, that’s why 1 of the major reasons we are really beginning to focus on the prognostic significance of measurable residual disease is how sensitive is that disease to therapy in determining what the long-term prognosis would be. But we don’t really have time for that discussion, so I’m just going to leave it at that if you don’t mind. I hope no one disagreed with that too much.

Transcript Edited for Clarity