The AML Treatment Horizon


Experts on acute myeloid leukemia offer closing thoughts and discuss emerging treatments in the field.


Naval G. Daver, MD: In closing here, I’m going to ask each one of you, aside from the menin inhibitors, what are the other agents in AML, or other trials in the next year [are you] looking forward to? Or what is most exciting on the horizon for you? I’ll start with you, [Dr Pollyea].

Daniel Pollyea, MD, MS: I think menin inhibitors are—every aspect that we discussed—top of my list [of] things that I’m excited about. Some other themes that I’m interested in are ways of overcoming venetoclax resistance, or what are mechanisms of resistance to venetoclax? I think there are a couple of interesting ideas out there. There are ways to target monocytes specifically. There are some monocytic targets that can be targeted with antibodies or maybe even CAR T-[cell]-type approaches. And that might include MCL1, which there’s still some efforts afoot to do that. I think that there’s other ways to do this with tamibarotene specifically, RARα agonist that seems to overlap with venetoclax resistance, and adding that to venetoclax (VEN) plus azacytidine (AZA) is actually the subject of an ongoing randomized study. I’m very interested to see what happens there. And then your institution, [Dr Daver], as well as ours, has a lot of interest in cladribine because of the potential there to overcome resistance to venetoclax specifically via the monocytic pathways. So that’s also not something not new, but something that is of high interest. Those are some things that I’ve got my eye on in the next year.

Naval G. Daver, MD: [Dr Wang]?

Eunice S. Wang, MD: I think that there’s a paucity of effective therapies for P53-mutant disease, so I’m very excited and awaiting the data for some of the CD47α-targeted therapies in combination with AZA +/- VEN, trying to come up with an effective targeted therapy for that subset. I know that data are hotly awaited, the results of the phase 3 in both high-risk MDS [myelodysplastic syndrome] and AML, specifically for P53-mutant [disease]. I’m also excited by immunotherapy. We’ve not had any effective for myeloid malignancies. And I think there’s the development of NK cells; that might be a better approach to target NK [natural killer] cells and macrophages as opposed to T cells, and harnessing the patient’s own immune system or allogeneic immune system for AML biology.

And lastly, I think this debate about replacing 7 + 3 with VEN is particularly relevant for our patient population. Similar to what’s happening in ALL [acute lymphocytic leukemia] using chemo[therapy]-light or chemo[therapy]-free regimens and moving away from 7 + 3 backbones to use, for example, VEN + AZA + FLT3 [inhibitor] or VEN + AZA + IDH [inhibitor] I think would be a huge advance in getting rid of that chemo[therapy] because I think there’s a number of patients who we are currently overtreating to try to get to those clinical end points in AML. And I think our data over the last 40 years suggest that there certainly are patients who are not benefiting from that approach.

Naval G. Daver, MD: And [Dr Erba].

Harry P. Erba, MD, PhD: I think I’ll focus on what’s new in FLT3-mutated AML. [Dr Wang] has actually led the way with the LACEWING study [NCT02752035] [investigating] if we can add a second-generation drug to azacytidine, if that alone would improve survival. And maybe in the high allelic frequency patients, there was some survival benefit, but really we have a lot of work to do in the older patients unfit for intensive chemotherapy with the [FLT]3-mutated disease. And hopefully some of the work that you’ve been spearheading at MD Anderson with venetoclax and second-generation FLT3 inhibitors will move the field forward for the majority of our patients who are older. But let’s not forget the younger patients, and those who we believe are fit for curative therapy.

And here I do think the second-generation drug quizartinib has shown a benefit in those patients. The QuANTUM-First [trial (NCT02668653)], as you know, has already been published, but hopefully is going to lead to the approval of quizartinib in the next 1 to 2 months. In that study, we took patients up to the age of 75 who were felt to be fit for chemotherapy. And they were randomized between intensive chemo[therapy] with quizartinib, consolidation and maintenance, or with placebo. And that’s because the study started before midostaurin was available in the rest of the world. And we saw a benefit. If you just look at the top-line results, it does not look much different than the RATIFY [trial (NCT00651261)] did. Your point is well taken there. But you have to remember that we took patients up to the age of 75, and 40% of patients were over the age of 60, and we only looked at FLT3-ITD, not FLT3-ITD and TKD. So, I think it’s important to realize when you look at the younger patients who [received] quizartinib, the hazard ratio there in that subset of patients was quite remarkable, being less than 0.7. It was 0.68.

So, I think there really is a benefit of quizartinib in the younger patients fit for intensive chemotherapy. And hopefully this drug will be brought to the market soon. We do need to watch for additive myelosuppression, we do need to watch for QT prolongation, but I don’t think those safety issues should overshadow the benefit of quizartinib. And finally, I would say, I think my patients will, maybe not enjoy, but tolerate quizartinib a whole lot better than they do midostaurin. So, it’s great to have options for our patients. And, as you know, gilteritinib is in phase 3 studies as well with PrECOG [LLC] and the Oban group. So, we’ll see in a similar population if gilteritinib, and of course crenolanib study, are positive, but those won’t read out for about another year.

Naval G. Daver, MD: I agree with many of these. I think menin inhibitors, hopefully, are the next [therapy] on the launchpad. I totally agree with [Dr Erba]. I think quizartinib is a fantastic drug from the days when Jorge Cortes, [MD, Georgia Cancer Center in Augusta University, Augusta, GA] was here; we’ve been using it phase 1, phase 2 [with] very good activity, very good tolerability. And, I agree, when you look at the [younger than] 60 population and only ITD, the hazard ratio does look very striking and promising in comparison to midostaurin. Now, the other benefit is, of course, even those who did not make it to transplant in the QuANTUM-First [trial] had a clear survival benefit in that subset, whereas this was not seen with midostaurin or CPX; in fact, where if you didn’t go to transplant, there was no clear significant survival.

I think it kind of speaks to the potency of that drug. Of course, I personally am very interested in the [anti-]CD47 [immunotherapy] magrolimab in 3 phase 3 [trials]. If there is anything in TP53 that’s progress, we will take it; whether it’s a few months or longer, whatever it is will be great. So we will hopefully see those data. And then as [Dr Wang] mentioned, I personally think immunotherapy is coming. I think we’re finally at that stage. A lot of NK, CAR T, bispecific CAR T, innovative approaches with CAR Ts are emerging. And then even antibody drug conjugates, [such as] CD123. We’re excited about IMGN632 and BPDCN [blastic plasmacytoid dendritic cell neoplasm]. It is in registration path and in AML efforts are ongoing. I think in the next couple of years we will start seeing more and more inroads with immunotherapy, which is something many of us have been excited about.

With that, we are here at time. I would like to thank you all very, very much. This was a great discussion. I personally learned a lot. Many of you have had a great experience with the menin inhibitors, so hopefully we will continue to see more and more progress and many of these move forward. I’d like to thank all of you for joining this lively discussion about the role of menin inhibitors and other approaches for management of acute myeloid leukemia, brought to you by Cancer Network. Thank you to the viewing audience. We hope you found this interactive discussion to be informative and beneficial to your clinical practice. Have a great day.

Transcript is edited for clarity and readability.

Related Videos
A panel of 5 experts on colorectal cancer
A panel of 5 experts on colorectal cancer
A panel of 5 experts on colorectal cancer
Arvind N. Dasari, MD, MS, an expert on colorectal cancer
Stacey Cohen, MD, an expert on colorectal cancer
Arvind N. Dasari, MD, MS, an expert on colorectal cancer
A panel of 5 experts on colorectal cancer
Aparna Parikh, MD, an expert on colorectal cancer
Stacey Cohen, MD, an expert on colorectal cancer
Carey Anders, MD, an expert on breast cancer
Related Content