Amir, I want to bring you into this discussion. If you have a young patient, 

 mutated, and they’ve relapsed, you know you’ve got to get them to transplant. Doesn’t it just make sense to give them chemotherapy to get them to transplant? Don’t these targeted inhibitors take longer? Do they get you in a deep remission?

 Eventually. If I may start with some principles that have been alluded to in passing, which are very important in my opinion when it comes to FLT3 inhibitors. One is tolerability. There is a marked difference between tolerability of, say, midostaurin versus gilteritinib. Or even sorafenib versus gilteritinib. Midostaurin does cause a good amount of GI [gastrointestinal] toxicity. It’s uncommon for me to give midostaurin to somebody and not have them at least have mild GI issues, whereas gilteritinib is much better tolerated. That’s an important consideration.

The other consideration is the type of leukemia patient. This is extremely important. Now that we’re doing NGS [next-generation sequencing] panels, we’re doing additional mutational testing. We’re discovering additional 

 TKD variance. Some of these FLT3 inhibitors, as Mark just alluded to, don’t really work. Sorafenib and quizartinib don’t have much activity.

What I oftentimes worry about in the community when we see patients coming in with 

 mutations or potentially treated with FLT3 inhibitors, for a mutation that would not be expected to respond to that 

 patient. Those factors are very important.

Finally, we talk about RATIFY, and this question has come up multiple times in the past. What is a dirty FLT3 inhibitor—let’s say midostaurin or sorafenib—doing to these patients? Is it mainly having a therapeutic impact through suppression of 

 mutations? Or is it potentially having other effects on other pathways that it may be inhibiting? It’s probably FLT3 because of the patterns that we have seen, but I’m not sure if that is completely the case. For example, the Soranal study showed that across-the-board patients without 

 mutations seemed to have some degree of response.

The quizartinib study showed that patients with FLT3 wild-type disease have a response. These are all questions that are yet to be fully answered. The answer to your question giving to a younger patient who may relapse, I’m not sure if it’s clear-cut that I would necessarily combine it with chemotherapy. That question has not been sufficiently answered, so I could not fault somebody if they want to put their patient on monotherapy with gilteritinib, with remission rates at approximately 50%; you could potentially decide to combine it with an HMA [hypomethylating agent]. The data on that is emerging. It’s not final, and we don’t know if it’s substantially better. I suspect it will be better, but I don’t have any definitive evidence to suggest that. I do not know if I personally would beat up a patient, even a younger one, with intensive chemotherapy, and gilteritinib, in the relaxed refractory setting.

Relapsed/refractory treatment for AML [acute myeloid leukemia], the remission rate, as we all know, hovers around 40% to 50%. Even in younger patients, it is not, depending on the timing of relapse, necessarily more impressive. My own personal preference is either give it as monotherapy or combine it with a hypomethylating therapy.

I would just jump in with 1 comment that sorafenib gets a little bit of a bad rap. It’s not the easiest drug to take. Mark Levis always says that all his patients’ hands and feet fall off. Mine don’t do that. But that drug has magical powers in the post-transplant setting that are different. I think both the scientific and clinical data suggest that the post-transplant relapses really might be something important to consider for some patients with sorafenib that could actually be different from the others. I just put that plug in that sometimes it’s just dismissed as old and not easy to take. But I think that specific setting is 1 that is actually quite interesting, especially in combination with HMAs.

Videos

Utilization of Second-Generation FLT3 Inhibitors in AML

Let’s move on to second-generation drugs. Mark, I’m going to come back to you on the development of both quizartinib and gilteritinib in this setting. And of course there’s crenolanib if we have time.

Yes. Actually the 3 drugs were coming in parallel. Quizartinib is the older 1 that was designed specifically as a FLT3 inhibitor. It had a bumpy regulatory course, but they finally emerged with this QuANTUM-R trial. Now quizartinib is a type 2 inhibitor. It does not inhibit the TKD mutations. It’s very specific for the ITD. Very potent, very selective, and for patients with relapsed or refractory 

 ITD AML [acute myeloid leukemia], they were randomized to receive a conventional MEK, or vicious salvage, or LoDAC [low-dose cytarabine], or quizartinib as a single agent.

Although that trial met its primary end point of overall survival, and the Japan regulatory agency thought that was fine, Europe and the United States did not. There was wringing of the hands over well QT prolongation. This drug seems very toxic, which is startling to any of us who have given it compared with MEK chemotherapy. Their point was it wasn’t a big enough improvement and that it really looked good only against LoDAC. But we can quibble over that. The simple truth is that it is an effective agent, and it is being studied in a different context as well in something called QuANTUM-First trial, which is up front. We can talk about that. But that’s quizartinib for the relapsed-refractory setting, a type 2 selective potent inhibitor.

The other 1 is gilteritinib. Gilteritinib was developed, and I like to use this analogy: The developers of gilteritinib watched all the mistakes made, and we were doing quizartinib. They just waited for us to spring all the traps and find all the screwups. Then they just marched on through very rapidly and casually developed a very good drug, which is in fact a type 1 inhibitor. Less potent but still very potent in vivo and really quite selective for the 

 mutation. It got approval for the relapsed-refractory setting and is now being studied up front versus midostaurin in combination with chemotherapy.

Finally, crenolanib is still back there. We’re waiting to see what’s happening with that drug. Really the focus, for practical purposes, is still on quizartinib and gilteritinib.

Second-Generation FLT3 Inhibitors in AML

Gail, let’s move on. Your patient comes in with newly diagnosed AML [acute myeloid leukemia] and has a 

 mutation. It doesn’t matter. I just heard that if it’s an ITD or TKD, we now add midostaurin. Why?

 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.

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.

 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?

You know in our setting, much like what has been referred to before, the eligibility criteria there for a chemotherapy 

-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.

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.

 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.

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.

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.

FLT3-Mutated AML: Midostaurin and Chemotherapy

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 

 and maybe other mutations where allotransplants should not be recommended?

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 

 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.

 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.

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, 

 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.

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 

 mutation. I’ve got to hit that with a FLT3 inhibitor.” But if I see an 

, then I don’t have to worry so much. But wait a minute, what if there are 4 other mutations, plus or minus the 

? I think it’s worse. The point is not to just buy into any reductionist view of this. We can’t just say, “

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 

 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.

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

 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.

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.

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.

FLT3-Mutated AML: Early Aggressive Therapy vs Transplant

I am Dr Harry Erba from Duke University School of Medicine in Durham, North Carolina.

Joining me today in this discussion are my colleagues Dr Amir Fathi, from Massachusetts General Hospital in Boston, Massachusetts; Dr Mark Levis, from the Johns Hopkins University School of Medicine in Baltimore, Maryland; Dr Gail Roboz from the Weill Cornell Medical College in New York, New York; and Dr Daniel Pollyea from the University of Colorado School of Medicine in Aurora, Colorado.

Today we are going to discuss a number of topics pertaining to contemporary treatment of acute myeloid leukemia [AML]. We’ll discuss the latest research in the field and the impact of recent clinical trials on making decisions around treatment selection.

Let’s get started on our first topic. I’m going to turn to you, Mark, to discuss the prognostic and predictive implications of 

 testing is often front and center when a new patient with AML hits the floor, so I think no one in the field who treats these patients doesn’t know that. Unfortunately we still encounter cases, particularly from the community, where 

 testing is either not obtained or obtained very late. As most people know, there are 2 broad categories of 

 TKD mutations. ITD is kind of common and bad; TKD is less common, less bad. The prognostic implications are, if you have an ITD mutation, you’ll do worse in general than a patient lacking an ITD mutation. TKD mutations, less so.

Nowadays, because we have an approved therapy, midostaurin, to be added to induction therapy, at least in a fit patient, the failure to recognize the presence of either of these mutations means you’re not administering a standard of care treatment that’s offering the patient a survival benefit.

You’re also not potentially starting plans for an allogeneic transplant, which may be indicated in the presence particularly of a ITD mutation, and you’re simply not aware of the response that could be expected to chemotherapy. If the patient is unfit, we know that patients, particularly with a 

 ITD mutation, don’t respond as well to HMA-VEN [hypomethylating agent and venetoclax] combinations, or if they do respond, response doesn’t last that long. Just starting with that, you’ve got to know about these things.

But you need to know even more. You need to know the amount of mutation present, and you actually need to know the quality of the specimen that you sent for analysis. Did you send peripheral blood that had only a few percentage points’ circulating blast? Or did you send a bone marrow sample that was pure blast? That’s actually going to impact your best guess of how much of a mutation is present. The mutation burden, as we call it, either the allelic ratio or the VAF [variant allelic function], particularly 

ITD mutations, really impacts prognosis in a big way. If you have a high allelic ratio or a high mutation burden of an ITD, particularly in the context of lacking an 

 mutation, that’s a disaster. That’s qualified as what we call ELN3, which in the ELN [European LeukemiaNet] classification system is for those patients with very poor prognosis, who do need to know that.

Finally, you need to know what mutations are present if and when the patient is relapsing. The type of FLT3 inhibitor you’re using may be impacted. If you’re going to use a FLT3 inhibitor that is a so-called type 1 inhibitor, it’s not going to work on the TKD mutations.

You’re not going to use sorafenib or quizartinib necessarily if there’s a TKD mutation present. It’s wrapped around your treatment response or prognostic response or plans for the patient, whether it’s a fit or unfit patient.

 Mark, is it adequate to wait for the next-gen sequencing panel, or are PCR [polymerase chain reaction] assays preferred for any reason?

Here’s the other big slipup that comes, and it’s even at our institution. Next-generation sequencing assays are typically used to identify the 

 TKD mutation because it’s a point mutation.

As you know, a next-generation sequencing assay may be delayed in coming back. Yes, at academic institutions we’re all getting them with a reasonable turnaround of, say, a week, so we can start the newly diagnosed patient who comes back with a TKD mutation on midostaurin. But if your next-generation sequencing assay does not come back for 2 or 3 weeks, which is still unfortunately common around the country, and this is what I’m still seeing, you’ve just missed the opportunity to add midostaurin to the induction regimen for a patient with a TKD mutation. We know those patients did quite well when midostaurin was added.

 ITD mutation is still mostly—not always but mostly—done with a conventional PCR assay. The turnaround time is quick, 2 to 3 days. Even your average commercial diagnostic lab will have that available sooner than the next-generation sequencing assay. They’re done differently. The mechanism of estimating the amount of allelic burden will vary according to the technique used. Actually, I would caution anyone to remember that the ITD allelic burden is prognostic, which does not necessarily mean the patient will predict a response to the combination of induction chemotherapy plus midostaurin.

In other words, it doesn’t matter what kind or how much of a 

 mutation you have for you to get benefit from the addition of midostaurin to induction chemotherapy. So don’t worry about applying rocket science to interpreting the mutation panel results. 

 mutation equals add midostaurin, and be aware of the finer prognostic implications of what kind of mutation and how much.

Amir Fathi, MD, Massachusetts General Hospital

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Utilization of Second-Generation FLT3 Inhibitors in AML

Second-Generation FLT3 Inhibitors in AML

FLT3-Mutated AML: Midostaurin and Chemotherapy

FLT3-Mutated AML: Early Aggressive Therapy vs Transplant

FLT3 Genetic Alterations in AML