Beyond 7+3: Redefining AML Treatment with Targeted Therapies and Trials

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. 

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Anjali Advani, a Hematologist specializing in the treatment of leukemia here at Cleveland Clinic. She was previously a guest on this podcast to discuss advances in the treatment of ALL, and that episode is still available for you to listen to. She's here today to provide insights on recent clinical trials for patients with AML, so welcome back.

Anjali Advani, MD: Thank you.

Dale Shepard, MD, PhD: Remind us what you do here at Cleveland Clinic.

Anjali Advani, MD: I'm a Leukemia Physician and Director of the Inpatient Leukemia unit, and then I also am a Chair of the Data Safety and Monitoring Board for Case [Western Reserve University].

Dale Shepard, MD, PhD: Very good. Well, we are going to talk about acute myeloid leukemia, and people like myself and other people listening in may just remember seven and three was kind of the standard AML treatment that we always reached for. Give us a little bit of idea of what has changed over the last few years in treatment.

Anjali Advani, MD: I think a couple of things. One thing that I guess I didn't have on the list, but might be good to talk a little bit about at ASH, the annual meeting this year, there was a large trial that was presented called the PARADIGM trial. And that trial was a multicenter trial actually looking at 7+3 versus venetoclax and azacitidine, which is a regimen we typically have geared more towards our older, unfit patients, at least that's where it's been approved. But the results of that trial were quite interesting in that some of the patients treated on that trial were younger. And actually the patients treated with venetoclax and azacitidine did extremely well.

Now, there are a lot of caveats there because venetoclax azacitidine is not thought to be a curative regimen. And so good risk patients were excluded. The thought was really many of these patients did go on to transplant, so venetoclax azacitidine is probably as good or maybe better if you're trying to get a patient in remission to go to transplant. Again, we need a little longer follow-up on those studies, but it was very provocative because typically that hasn't been something we've thought about.

And so I think going forward there are, within SWOG and the NCTN, there are some trials trying to kind of look at the question for those patients that are young, but have, for example, adverse risk chromosomes or bad biology, or is treatments such as azacitidine venetoclax probably potentially better in that setting. So, there are randomized studies being done kind of to look at that question. And I think besides that now, there's also a lot of new targeted therapy that wasn't available, you know, way back, 20 years ago, even when I first came here. So for example, for FLT3, which is a very common mutation, we see in about 30% of AML, we now add tyrosine kinase inhibitors. Typically, we were using midostaurin, but there's another one that now has been approved on the upfront setting called quizartinib, and that was based on the quantum study.

And then two studies we've had here, which have been very kind of interesting and exciting, menin inhibition has been of a lot of interest. So there is a pathway that basically menin is thought to be important for promoting leukemic cell growth, but it turns out that it's not limited to just one specific mutation. For example, NPM1 mutations, which are very common and are about 40% of AML, and then MLL rearrangements, which we see in both AML and ALL, both of those work through a pathway called HOX-MEIS. And it turns out that if you inhibit menin, that basically kind of shuts that pathway down. And so there are several now menin inhibitors in clinical trials by various different companies trying to really target this pathway.

Two of the drugs have actually been FDA approved in relapsed refractory disease. Ziftomenib is FDA approved and NPM1 mutated, and then revumenib has also been FDA approved in MLL and NPM1 mutated disease. But the trials that are ongoing right now actually started before these drugs were FDA approved even in that setting based on the fact that relapse studies looked very encouraging. And basically now the new trials are trying to look at incorporating ziftomenib. For example, in the Kura trial or the KOMET trial, which is one of the trials we have open here kind of as upfront therapy. And then there's also a combination trial in relapsed and refractory AML, so it's really interesting and exciting. The thought is maybe if we incorporate these drugs upfront, we'll have better responses and hopefully better outcomes is kind of the thought behind it.

Dale Shepard, MD, PhD: Yeah. We'll talk about a couple of those trials here in a second, but you mentioned some of these mutations like FLT3 and MPN1. So, how has the approach to patients changed? Because I remember, way back when I was a fellow, patient rolls in and you got to get started fast. And so how do you incorporate these genetic changes, the markers? How do you approach patients now so you can get things done quickly, but yet more targeted?

Anjali Advani, MD: Yeah, no, that's a great question. And something we still are struggling a little bit with. So some of the trials are non-targeted and we'll talk about one of the other trials that is kind of mutation agnostic, but your question is very good. Our pathologists now here have something called a rapid NGS panel. Basically, what happens is there is a little bit of a delay in that. Basically, only the pathologists can order that, so they have to basically confirm the diagnosis either by blood or bone marrow. And then once that happens, they order this rapid NGS, which is a limited mutation panel, but looks at things like FLT3 and NPM1 and MLL. And so technically we should be able to get that back in about four days. Now, the question is, is that business days or is that... And so that's where sometimes if it happens over a weekend, that can be a little bit of a delay. They have been really good. When we reach out to them, they really are trying to get those results back quicker.

Nationally, the study MyeloMATCH, which is very targeted for specific mutations within the NCTN, those results, you get within 72 hours, but you need to be enrolling a patient on a MyeloMATCH trial, but they're actually, and that's 72 hours regardless of weekends. So, the hope is kind of in the future and something we've kind of talked about within our group, it is a little bit of a challenge because you have to decide, is the patient, kind of getting to your question, stable enough.

Some of the trials, again, are mutation agnostic. The ones like the menin inhibitors, some of them are nice. For example, the KOMET study does allow you to start in some of the arms, the azacitidine and venetoclax, and then you just have to enroll the patient by day eight, so some of the studies are nice like that. Some of the induction trials with 7+3, there is a trial Dr. Mustafa Ali has here with Syndax, which is seven and three plus or minus revumenib. And that study also, you're allowed to start the chemo. You just have to make sure you start the right backbone regimen and that you're compliant with the protocol, so.

Dale Shepard, MD, PhD: But at least you can get started and then you can add in a trial drug?

Anjali Advani, MD: Exactly. But you just have to be very careful. What's the anthracycline? What's the dosing of the Ara-C? So, that's something within our group. We're actually trying to now make flow charts so that if someone is on service, it's sometimes hard to remember all those nuances and we're trying to kind of have something where it's all written down in one place.

Dale Shepard, MD, PhD: How have the newer markers, genomics, how have those changed how you think about moving toward transplant?

Anjali Advani, MD: I think the mutations really help you kind of refine your plan for transplant because many of these mutations now may be higher risk. And so I think we're probably sending more patients to transplant that before we may have just known, "Oh, their chromosomes are normal." Right? And didn't have all that mutation testing.

Dale Shepard, MD, PhD: And then you mentioned trials that are going on with relapsed or refractory. Do those tend to be people before transplant or after transplant or both?

Anjali Advani, MD: Those trials typically include both, but one of the problems is if it's post-transplant, they usually have to be at least 90 days post-transplant and not have active graft versus host disease or beyond immunosuppressants, so that can kind of limit it for some of those patients.

Dale Shepard, MD, PhD: Gotcha. So, there are a couple of trials, um, you had mentioned the menin inhibitor and there's a trial related to that. Tell us a little bit about what's going on in that space with trials.

Anjali Advani, MD: One of the trials, where I'm the principal investigator here, has been the KOMET-07 trial and that trial is for both newly diagnosed and also has relapsed refractory and is looking at both NPM1 mutated as well as MLL rearranged patients. And then it has had both intensive chemo arms as well as the non-intensive with venetoclax and azacitidine. And the one arm we don't have open yet, which will hopefully be open soon, there is also going to be a, which this is open other places for patients that have NPM1 mutation and FLT3 mutation, it's going to be 7+3 plus quizartinib, which is a standard regimen we would use for FLT3 mutated AML, but then it's adding ziftomenib in there, a phase one dose escalation.

Dale Shepard, MD, PhD: So, as I remember, things like 7+3 tends to be somewhat rigorous. As we are adding more and more drugs, what does the toxicity profile look like?

Anjali Advani, MD: Yeah, that's a great question. I mean, so far it's been pretty well tolerated, but I think the main thing we seem to see is probably a little bit more myelosuppression, so just lower counts potentially for longer. It seems to kind of vary. There's some people that seem very, very sensitive and there are other people that you don't really see issues. If you look at most of the trial reports, they don't really comment on it, but I'd say just in our experience, we have seen some people that have had prolonged count recovery. And so I think it is really important, as we kind of go forward, being careful with the monitoring rate really, seeing what happens. And again, although the results look very good in terms of response rates and MRD negativity, there is going to be the KOMET-017 trial, that I think is already open at places, that's going to be a randomized study. And I think ultimately to kind of answer these questions, you're going to need the randomized studies to check both for safety and also, you know, "Are we going to improve overall survival event-free survival?"

Dale Shepard, MD, PhD: And I guess if you have regimens that are more myelosuppressive, is there concern about ability to transplant if there's a relapse in that setting?

Anjali Advani, MD: If they're myelosuppressed and you're able to go right onto transplant, that shouldn't be an issue. But your point is good, if you're myelosuppressed and you're not ready to go on to transplant yet and you're in this gap and you're not on any treatment, then I think that's where people can run into issues.

Dale Shepard, MD, PhD: Yeah. What other trials are you particularly excited about?

Anjali Advani, MD: Another one we have open here is with an anti-CD70 monoclonal antibody by a company called Seattle Genetics. And CD70 is overexpressed both in MDS and AML. And so this trial has actually been going on for a while. It was evaluated in relapse refractory disease. The antibody was looked at as a single agent. It was looked at in... Yeah, we talked about relapse refractory. Now, the study is open in MDS, that's high risk in AML. So, in high risk MDS, it's actually a randomized study, azacitidine, which would be our standard of care versus azacitidine plus this anti-CD70 antibody. So, it'll be very interesting, because there have been multiple phase two studies in MDS that have looked very encouraging with other drugs, and then the phase three studies have all been kind of a bust. And so you know, there is hope that, you know, hopefully this will be promising, we won't know until really we see the results, so that study is accruing.

And then in AML, this trial is looking at azacitidine venetoclax, which would be our standard plus the anti-CD70 antibody, and that is not randomized. So, that'll be very interesting too, kind of to see what the... The nice thing about the anti-CD70 antibody, really the main toxicity is infusion reactions, but once you kind of have the pre-meds and all adjusted, which over time as this trial's gone on, it's really been very well tolerated. So, yeah, that'll be exciting.

The other thing that had been of excitement in MDS, which I guess some people are still using, but was the VERONA study, which looked at the addition of venetoclax to AZA and MDS, and that trial was negative. Although there's some question, there may be subgroups of patients, there may be some benefit there.

Dale Shepard, MD, PhD: Excellent. I guess when you look at the progress, what's still missing? Are there particular populations, young, old, certain markers, where do you think there's still the biggest need?

Anjali Advani, MD: I think probably the biggest area has been P53 mutated disease. That's an area where there've been a lot of trials done and there's still some hope. Possibly, the anti-CD70 antibody, maybe it'll be good. Again, they'll have to look at that cohort and further evaluation in the studies that are ongoing. There's another drug that is targeting CD123 that's an antibody drug conjugate. They actually are looking specifically within one of their cohorts in AML, venetoclax, azacitidine, plus that antibody-drug conjugate, so that'll be interesting. Again, the issue's going to be kind of doing what happens when you do the phase three studies, because there was some interest in a lot of the anti-CD47 antibody drugs, and then it just didn't pan out. But P53 mutation tends to be tough because even when we get those people in remission and take them to transplant, their rate of relapse is very, very high.

Dale Shepard, MD, PhD: As you're looking at things that move away from traditional chemotherapy, maybe more effective therapy for older patients?

Anjali Advani, MD: Yes, I think definitely. I think a lot of these targeted agents, they're better tolerated. And the hope is maybe if you combine them and people get a very deep remission rate, could they have better long-term outcomes?

Dale Shepard, MD, PhD: Fantastic. I got to tell you, back in my fellow days, which of course is the last time I treated anyone with leukemia, it was very straightforward. It was start chemo, and it seems pretty complex now, and that's a good thing for patients, so appreciate you sharing your insights today.

Anjali Advani, MD: Yeah, absolutely. Thank you.

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