iwAL 2024 | Updates on established therapies in AML – Part 2

Naval Daver:

Hello, my name is Naval Daver. I’m a faculty in the Department of Leukemia in the Anderson Cancer Center. It’s a pleasure to be here with my colleagues and friends.

We had a morning session focusing on targeted therapies and standard-of-care options in the setting of acute myeloid leukemia. This is at the iwAL 6th edition meeting in Phoenix, and I’m going to briefly present what I spoke about.

I spoke about frontline treatments in the FLT3 space. There’s a lot of new emerging combinations there, the new standard of care with either quizartinib or midostaurin added to backbone intensive chemotherapy.

We’re also looking in older AML patients who are not fit for intensive chemo at potentially adding targeted therapies like FLT3 inhibitors to HMA/VEN, with the same time reducing the doses of the components to allow for better safety and tolerability, as well as using molecular MRD to determine duration of the treatments and eventual path to transplant.

I’m going to turn over now to my colleagues, Dr. Craddock first, who’s going to give us a brief overview on what he presented at this iwAL meeting, please.

Charles Craddock:

Yes. I think some of the important points, Naval, that came out during the discussion after your talk, were the recognition that we have an opportunity to rethink what the optimal induction regimen is in fit adults with AML.

And I think there were two examples that were cited. The first is that in older fit adults, the majority of these people who will have allogeneic transplants, their only curative option, at the moment, their outcomes with standard intensive chemotherapy induction are not good. The CR rates are not great, and there’s a lot of treatment-related mortality.

So, Dr. Cortes, in our session, presented really important data with CPX-351, showing that the survival benefit from CPX-351 in people with secondary AML over 60, the pivotal study compared with DA came from patients who went to transplant.

And so this set a ground for some of the work that’s coming out of your institution using venetoclax-based regimens as an induction strategy.

And I think we’ve been particularly impressed with the fact that there’s an ECOG study that is accruing comparing VEN+AZA with induction chemotherapy, but also the data from your group with cladribine-venetoclax from Tapan Kardia.

And so we talked about how the UK in collaboration with MD Anderson leadership is going to do a randomized study in patients with high-risk AML of any age who are fit for transplant, whose outcome with standard induction and transplant is poor compared with the cladribine regimen, adding some tagraxofusp.

And I think this is really a potentially breakthrough study. I think it’s got potential to improve outcomes for these patients who need to go to transplant for cure in three ways.

One is I think there is a very good chance it’ll give it a higher CR rate, so more patients will go to transplant. Second is I think there will be less treatment-related toxicity, and so transplant will be better tolerated.

And finally, I think it’s plausible that patients will go into transplant with a greater rate of MRD negativity reducing the relapse rate. So that I think is a very important strategic breakthrough.

And then lastly, we talked again about a collaboration between the UK and the MD Anderson looking in older adults with FLT3-mutated AML, building on the data from your institution, that using a venetoclax-azacitidine triplet with either gilteritinib or quizartinib, again, gives you high CR rates and modest toxicity.

And so our plan in this study, as a partnership, is to randomize US or UK patients to receive that triplet or DA quiz. The majority of these patients going on to transplant. I think it’s only through randomized studies such as this that we’re going to change that induction landscape, which I think is the biggest possible win we have improving transplant outcomes.

Naval Daver:

Thank you very much, Charlie. And Dr. Perl, you spoke about relapsed/refractory FLT3, I really liked your talk, and how the landscape is changing and I think that’s very important. So could you highlight what you’re seeing in your clinic and where you think the relapsed space will be and how should we optimally manage these patients?

Alexander Perl:

I think one thing that’s exciting is relapsed FLT3-mutant AML used to be a really big problem because it was frequent, it was very hard to manage and we had limited tools.

And then with drug development, we now have more tools to attack it. And with those drugs being developed, they’ve moved earlier in therapy and with them coming earlier in therapy, the natural history has changed.

So what we’re actually seeing both in my clinic, I think everywhere, is that this population is less commonly seen. When we do see it, it looks different than what we’ve studied in the trials, and that actually introduces some challenges because we have to take data that were collected at a different time in therapy and interpret them in the modern world. Patients have had prior venetoclax, patients have had prior midostaurin or even gilteritinib early on in therapy.

And now as there’s emerging data that the role of transplant may be changing for FLT3/ITD-positive AML, quizartinib maintenance is approved, and this may actually create a new population that we’re seeing when we see relapses after that.

I don’t think we know really as well what the resistance patterns to the front line therapy of say 7+3 plus a TKI are really looking like as to how that changes how these patients will respond to one therapy or not.

We’ve looked a lot at combining agents with gilteritinib in the relapsed space, and that certainly has increased response rates but has also increased myelosuppression, and whether that’s better than gilteritinib alone for many patients is still I think a question.

I’m currently actually trying as much as possible to get patients to transplant if they’ve not had a transplant before or DLI or whatever is most appropriate. And I think the best way to go from point A to point B is really what’s controversial in the field still, and we don’t yet have a comparative study to say what the right answer is.

Naval Daver:

Yeah. Great. And then Dr. DiNardo, you focused on IDH, another big molecular population, and the frontline approaches both for fit and unfit. And could you just give us a summary on your thinking there?

Courtney DiNardo:

So I started by talking about our younger patients who are fit, who have an IDH1 or IDH2 mutation, which is about 15 or more percent, so it’s not non-significant, and talking about how there’s not a lot of data yet, but we’re starting to, we’re anticipating soon, a large randomized result of 7+3 with or without an ivosidinib or enasidenib for IDH1 or IDH2, and kind of talked about how some of the initial Phase I data does look quite positive, but again, without that control to be confident.

And then also adding venetoclax, right? This is more and more becoming a thing, intensive chemotherapy with venetoclax, and highlighting the fact that IDH-mutated patients, especially IDH2, do incredibly well with venetoclax addition, so that’s likely going to be another very effective strategy.

And then we pivoted to talk about, well, but what about our patients who are in that kind of borderline fitness or just because you’re fit for chemo, does that mean that that’s what we should do?

And talked about our triplet experience with HMAs and venetoclax and IDH inhibitors, and these were some of the first triplets that we did and we have the most experience.

And I highlighted that it was a good first experience because when you add the IDH inhibitors, you don’t have as much myelosuppression or toxicity. So it’s a well-tolerated combination in general and just talked about how that really does seem to be leading to really impressive numbers of responses, MRD negative responses, durable remissions and several ongoing studies coming now soon that actually Dr. Craddock had highlighted in the next session about how we’ll have some randomized data coming soon.

Naval Daver:

Yeah, I think one of the key messages as Dr. Craddock likes to use adages is just because we can do something doesn’t mean we should do it. I think that is really the application for intensive chemotherapy.

I don’t know why we think of it as somebody has to prove themselves as not capable of tolerating toxic intensive chemo for us to move to the next level.

If you spoke to an outsider outside of the field, they’d be like, shouldn’t be the other way around that you should only use the toxic intensive chemotherapy if you truly believe it’s better than what is available. And I think that’s kind of because for 45 years that’s what we had, it’s almost like a child going to college that we just can’t let it go because it may be the next best step, but we’re just, no, no, I can do this so well, it has to work and I’m taking risks.

But I think finally the ball is moving, whether it’s going to be with the FLT3 triplets, the menin triplets, the IDH triplets, combinations and like anything, of course, it’s a work in progress. I think a lot of nice discussions came up by colleagues where they asked, well, how long do you do triplets? Is it three cycles? Is it four?

Can you use molecular MRD to de-escalate as they’re doing in CLL and ALL? Can you avoid transplant in certain patients based on molecular MRD data?

And we don’t have the answers because a lot of this has happened literally within the last one and a half year, but as was mentioned, we have the tools and we have the patients and now we’re going to have trials looking forward at that.

So let me ask you, Courtney, we talked about the HMA/VEN FLT3 versus intensive chemo FLT3 in this 50 or 55 to 75, which I really think is the trial we want to do not in the eighty-year-old. I think that’s a very tough proposition. Do you think that’s something that we could do in IDH? Is that worth looking at?

Courtney DiNardo:

I do. I think especially because IDH patients in general tend to be older on average and so this is a population that really defines the IDH-mutated AML population.

They are in their sixties and seventies, and so they are potentially fit, but maybe would benefit just as well from lower-intensity strategies.

And I personally suspect that they’re going to do just as well with triplet strategies and with less toxicity. And so I wouldn’t be surprised at all with a positive outcome of one of those studies.

The challenge is just kind of organizing and going through the challenges of doing such a randomized trial. But I think the one thing that is challenging, which you had mentioned, is transplant.

So that is what complicates all of these decisions because we know that intensively treated patients who become MRD-negative often don’t require a transplant in first remission. And we don’t know that with HMA/VEN combinations or triplets.

And so when we’re taking these patients who could have been fit and we’re doing lower intensity strategies, I think we’re destining them, at least for now, to a transplant that they may not have needed otherwise. So that’s a really important consideration.

Naval Daver:

Yeah, I think transplant, I think one of the other things that’s not just at this meeting but in the last few years has emerged is that transplant is probably more and more the key destination than it even was.

Part of that is because transplant procedures, just like everything else, we’re getting better. There’s better understanding of how to manage toxicities. There are better antivirals, there are better post-GvHD medications. So in our experience in our institution, we have worked with our transplanters and we’re doing 10 to 15 percent more transplant today than we did eight to 10 years ago, and this keeps going up. So to you, Dr. Craddock, the question is, do you think, and I kind of asked this in the meeting as well, with these molecular techniques, whether it’s in younger or older, we’re going to start seeing movement like ALL where we start sparing transplant? How would that look? Or do you think it’s just too early and we shouldn’t be changing any practice yet? And let’s take FLT3 and NPM1 as the two molecular markers.

Charles Craddock:

So let me just reflect on your earlier comments that this is the time for a fundamental reevaluation of the optimal treatment package for fit adults with AML.

And it’s absolutely true Naval, because two things have happened in the last five years. One is we actually have different drugs and we can do something. So this would’ve been an idle discussion 10 years ago.

And the second pivotal thing is that, it is possible to take most fit adults to transplant with relative safety. And again, that’s very different from 10 years ago. So I think you’re completely right.

You need to think, as Courtney was saying, have you got patients who will do well with intensive chemotherapy or plausibly actually stay away from transplant? Of course. But otherwise, if transplant is the curative destination, and as Sasha was saying, it is for many patients, then the question is what do you need to make a happy transplant? And one is the CR, and two is it’s a fit patient.

And so actually instead of obsessing about the chemotherapy and its long-term benefit applied simply as a chemotherapy, you have to think about how does it fit in with optimizing transplant, realizing that the VYXEOS (daunorubicin/cytarabine) randomization showed dramatic improvement in transplant.

So I’m just echoing what you said. We will, I’m convinced Naval, become more sophisticated in understanding which patients can be spared a transplant. And let’s be clear, if we can avoid a transplant, we should do that.

And I think the data in NPM1-mutated patients is emerging. In patients who are NPM1-positive FLT3/ITD-negative, I think there’s really good data from a number of groups and also randomized study in France by Balsat. That if you are MRD negative, you don’t need a transplant and you do well. But if you are MRD positive after a couple of courses, you do. Easy.

I think the area where there’s a little bit more contention is if you are NPM1-positive FLT3/ITD-positive, and there’s some very really important data, I think both from Peter Falk and also from the UK group showing that, in younger patients who are NPM1-negative, using it as a surrogate marker in that population, their outcome, and this is in overall survival, is equivalent to the patients who were transplanted.

There’s a few caveats: that these people didn’t get a FLT3 inhibitor, it is a single data set, the UK data, and thirdly is it depends on these people being salvaged, right? Correct.

And actually salvage is not a great procedure to go through and then transplant. And so of course you wouldn’t see that benefit. You wouldn’t see the equivalence of using RFS as the endpoint.

But nonetheless, I think increasing scrutiny on particularly which younger patients who show a very good MRD response can be spared of transplant is important and will be part of our emerging landscape.

Alexander Perl:

So just to follow up on that, I mean in my practice for the FLT3, say FLT3-ITD positive patients, where we used to uniformly recommend transplant in first remission, pretty much across the board there’s emerging stories saying that for patients with optimal response who become MRD negative early after intensive therapy, and again, the younger patients, it doesn’t mean they may never need a transplant. But we may not need it in CR1, there’s better salvage options for these patients.

But one thing we don’t know is, if we give maintenance after that transplant, how long do you need it? Do you need it indefinitely? Do you need it for two years? As we gave in Morpho.

We’ve always erred on the side of giving maintenance to those patients. It really does commit to a much longer treatment course. It’s just a different approach that we have.

Charles Craddock:

And I think the other philosophy that’s important is, if you have a well-matched donor and a fit patient transplant toxicity is much less than it was. So you have to think very carefully before you eschew a potentially curative therapy.

Naval Daver:

I mean, we’ve talked about this a lot towards Sasha is saying, and Charlie and me talked about it, the durations of therapy and Gail brought this up in the discussion as well, this is probably going to be the next, when we didn’t have good therapies and the survival was 20%, we didn’t care about the duration of therapy. Whatever we had to do, we did it for our patients.

Today we’re getting to this point where 70, 80% up front, NPM1, FLT3 is getting there. So we may be able to curtail treatment safely in certain patients.

So I think that that’s going to be a really key area because if you take a patient, as Charlie said, with intensive chemo, FLT3, three or four cycles, transplant and two years of maintenance- the total duration of therapy is two and a half years approximately.

If you take somebody with HMA/VEN + FLT3 or HMA/VEN + IDH, you give them three, four cycles, you take them to transplant, they get maintenance, it’s the same thing. But it’s the people who don’t get transplant where there’s a huge confusion.

If you’re do intensive chemo, three or four consolidations with FLT3, are you going to do one year, two year, three year maintenance? QuANTUM-First did three years. If you’re HMA/VEN + FLT3, it’s even more complicated. You’re going to do 3, 4, 5 cycles, probably not more than that. It’s hard to give more than that for sure, but then you’ll de-escalate. Then what do you do? Another year?

So in the end, all of these are pretty much a long-term proposition, except maybe for those patients who go to transplant, molecular negative, where we may be able to not give maintenance based on the MORPHO data. That may be the only short period. So I think they’re all ending up in two to three years.

Courtney DiNardo:

But this is where the pace of translational development and the pace of technology and MRD is going to be really impactful, right.

Because we don’t know the answers yet, and so we are defaulting to longer maintenance because we don’t want our patients to relapse. To your point, relapse is no good. They have to go through all sorts of struggles to potentially have a durable second outcome.

But if we can be better at our MRD technology and be able to link that specifically with risk of relapse, I think that’s where the field is going to be in another year or two. We’ll be able to better define who really is cured and who really needs the longer maintenance cycles.

Naval Daver:

Yeah. Well, I think that was great discussion and looking forward to the rest of the meeting. And we have many, many sessions to go, so we got to save some stamina. So with that, I’m going to thank you all very, very much and see you next time. Take care. Bye.