Video

FLT3-Mutated AML: Midostaurin and Chemotherapy

Harry Paul Erba, MD, PhD: Gail, let’s move on. Your patient comes in with newly diagnosed AML [acute myeloid leukemia] and has a FLT3 mutation. It doesn’t matter. I just heard that if it’s an ITD or TKD, we now add midostaurin. Why?

Gail J. Roboz, MD: The RATIFY trial, which took a long time and a lot of centers to accomplish, really demonstrated a survival benefit with the addition of midostaurin to standard conventional chemotherapy. That very quickly was adopted as the standard of care. We were really ripe for looking for something to add to 7+3, first of all. Secondly, that was ushering in an era of targeted therapy. So you have these patients who are coming in. Many of them are actually quite proliferative and scary. There is a proliferative signal conferred by the mutation. These are the ones who come in sometimes with a 150,000 per mm3 white blood cell count, a head bleed, or other things that are going on.

I think Mark’s point about get the testing done is to figure out what you’re dealing with. We’re going to add midostaurin. Midostaurin is generally quite well tolerated. I would say there are some rashes, some GI [gastrointestinal] toxicities that can happen. There’s nausea. There’s vomiting that can happen, so you have to look out for that. But in general, the overall aggregate data showed that there was a clear win with respect to survival. Actually the suggestion, which was alluded to a few minutes ago, is to use FLT3 inhibition throughout. FLT3 as part of the initial therapy.

If you’re not getting a transplant, they’re getting FLT3 inhibitors as part of consolidation and even subsequent maintenance therapy. After transplant there is a strong trend for maintenance too. Transplant is not, unfortunately, actually the end. It’s “one and done,” but there’s ongoing FLT3 inhibition that is largely practiced, not completely with data but with strong suggestive data that ongoing FLT3 inhibitors might be a good idea for some patients even post-transplant. We’re waiting for the confirmatory data for that.

Mark J. Levis, MD, PhD: But not necessarily with midostaurin.

Gail J. Roboz, MD: Right. For now we just have to be careful. Obviously, the news is whether gilteritinib, for example, would be moved forward. And for induction consolidation, post-transplant maintenance, what would be the role there? Is it better to use the midostaurin? Is it better tolerated? For right now midostaurin in combination with chemotherapy is the up-front standard, but there is the anticipation that gilteritinib may have a lot to offer in both up-front and post-transplant maintenance.

Harry Paul Erba, MD, PhD: Dan, let me ask you a question here to pull you into this conversation. You know midostaurin maintenance is approved in Europe but not in the United States based on the same RATIFY trial data. This is because of the peculiarities of the design, where patients were rerandomized at the time of maintenance assignment. Do you use midostaurin maintenance? Is there anything that makes you think it’s really valuable here?

Daniel Pollyea, MD, MS: You know in our setting, much like what has been referred to before, the eligibility criteria there for a chemotherapy FLT3-positive patient who gets induction plus midostaurin—if they get into a remission, there is going to be a transplant. There are all kinds of contingencies and bumps in the road that could take you off that path. But for the most part, it’s not a big issue for us for that reason. If a plan from the get-go was for them to go through reduction, then they’re going to go to a transplant and move on from there.

Whether there should be a roll for post-transplant maintenance with an agent, Amir and Mark already kind of referred to that. For us it’s a sphere without a real treatment for that reason. What I will say is that we’re in that situation where if a patient gets induction, gets into a remission, and does not go to transplant, we would consolidate that patient with midostaurin. We would follow essentially what the RATIFY study randomized patients to with a maintenance program with midostaurin, even if that’s not the labeled indication.

Mark J. Levis, MD, PhD: My objection to that approach, which is a reasonable approach, is that we know more than half the patients who are on this bad-smelling pill come off it because they can’t tolerate it. In fact, the mLSG-15 study basically had 57% of patients leave the treatment because they couldn’t tolerate the stuff. So it isn’t that we don’t like it.

Harry Paul Erba, MD, PhD: Well, you opened that can of worms. The FDA doesn’t want to be ageist, but the RATIFY trial was in patients up to the age of 59 years, not 60 years or over. The data that was used to support the use in older patients is the German AML1610 study that took older patients.

Mark J. Levis, MD, PhD: To 65.

Harry Paul Erba, MD, PhD: But only based on historical comparator was it better than chemotherapy without midostaurin. You’re right, they saw more toxicity in those older patients as well. But at the end of the day I’m still impressed by Dick Larson’s presentation of what happened to patients who were known to be on midostaurin for maintenance. When they stopped it, there was this rapid 25% decrease in the disease-free survival, which suggests maybe in some patients it’s doing some.

Mark J. Levis, MD, PhD: And patients relapse. We’re going to see this data soon. Patients relapse from that treatment with the ITD mutation still present. About half of them will relapse. When they relapse they still have the ITD there. So there’s potentially a role for it.

Transcript Edited for Clarity

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