Expert Discusses Need for a More Targeted Approach in Acute Myeloid Leukemia

Alice S. Mims, MD

The current task ahead of hematologists/oncologists who treat acute myeloid leukemia (AML) is selecting the most optimal upfront strategy upfront from a large pool of therapies, according to Alice S. Mims, MD, who gave a presentation during the NCCN 2021 Virtual Congress: Hematologic Malignancies (NCCN Hematology).

Between 2017 and 2018 alone, 4 new treatment strategies entered the landscape, and they are all intended for patients with different AML characteristics. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for AML offer recommendations of how to approach treatment for these patients. Still, Mims explained that some subgroup, like those with comorbidities and/or are elderly require novel treatment options.

In an interview with Targeted Oncology™ during NCCN Hematology, Mims, Acute Leukemia Clinical Research Director and associate professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center – James, discussed targeting biomarkers in AML, and upfront disease management.

TARGETED ONCOLOGY™: Can you discuss genomic testing in AML? What targets should physicians be looking for today?

First and foremost, genetic testing really should be done on all patients upfront. It really helps us know what treatment options are available, and it leads to better discussion with them about those options and helps them be more involved. There are some patients who can't wait necessarily for results to come back. But I think as we're getting faster and faster, with getting results back, especially for those important mutations, like FLT3, IDH, and TP53. What I hope is that those will all get to be a part of most patient discussions for treatment options.

What novel targets are being researched currently?

What I would say is some novel targets that are being looked at are things such as MENIN inhibitors, and things like targeting CD47 with antibody therapy on CD3, CD123 bytes. There's CAR T cells. So, there's a lot of different things that are ongoing that we hope will really make a difference. For these patients, especially as we continue to make progress, [it's important to remember] most of the therapies that have become available as of late are not curative.

Can you discussion the key updates that have been made to the NCCN guidelines for AML this year?

With the NCCN guidelines, and some of the updates for the management, things have become a lot more complicated, because we have more available therapies than the prior 7+3 or hypomethylating agents.

So, I think a lot of the changes have been dividing things up based on age and outcomes. Then looking at that genomic testing and making decisions based on those results for patients who are able to wait. I also think, there have been a lot more recommendations for older patients, who haven't been induction candidates before. The recommendations talking about repeating genomic testing at time of relapse disease, as patients could develop clonal evolution where they may have gain or targetable mutations that may be new options for them that necessarily weren't options in the upfront setting. So, I think those are a lot of the things that have come about in the NCCN guideline changes.

What is important for physicians to know about your presentation?

I talked mostly about changes in the upfront setting. So, a lot of my points were, how do you make decisions for those patients in the upright setting, and how I think about things?

I talked about the different regimens, and in the upright setting for those who are intensive induction candidates, most of them are anthracycline and cytarabine-based backbones while those are not. Those who are not have hypomethylating agents plus BCL-2 inhibitors or hedgehog inhibitors available to them. And there are a lot more options for those patients.

I did talk a little bit about some of the newer therapies that are coming. So, 1 combination strategies for those intensive induction candidates is adding targeted therapies or immunotherapy. I think another thing that's really exciting is looking at all oral combination regimens, especially with the oral hypomethylating agents becoming available, because I really think they help some patients with quality of life. I think quality of life is very important, especially if you're talking about treatment, that's not in a curative intent.

Thinking of new therapies and the lack of FDA approvals in AML recently, what promise os being shown with the agents that are currently in development?

I think some of the regimens that we're excited about one in particular, is targeting CD47, like magrolimab. That seems to have potentially increased responses in TP53-mutated AML. And I think that population doesn't respond well to any of our typical treatment regimens. So, that's really the patient population we want to do a better job with.

As we're seeing potential therapies that may help that population, we're all very excited about that, some other regimens are addressing measurable residual disease. As we're learning more about that in the field of AML and really learning if you can get to where you can't detect disease, even at low levels on B, those patients need to move forward with transplant.

I think some other regimens that are I think will be exciting is having the IDH inhibitors combined with intensive induction therapy and the upfront setting. And I think a lot of us are excited about MENIN inhibitors, in particular for MPM1-mutated AML and MLL-rearranged AML as that those agents have shown single agent activity in the relapsed/refractory setting. As more data evolves with those inhibitors, I think people are excited to see how they'll do in the upfront setting combined with either hypo methylating agents and BCL-2 inhibitors or with intensive induction therapy as well.

How do you envision the treatment of AML evolving over the next 5 to 10 years?

A lot of research is looking at triple combination regimens. So, looking at if you can combine just different small molecule inhibitors, either in the upfront or relapsed/refractory setting. And I think as we learn more about these, what I'm hoping for, is we can get away from things like intensive induction therapies that have a lot of toxicities. Many patients aren’t candidates for these therapies because of comorbidities and the age typical average age of diagnosis for AML, so I think we're going to have a lot of room to go for AML.

We've made a lot of progress since 2017 or so when we had all these agents approved, but I think we're going to continue to make a lot of advances. It's an exciting time for our patients and to the field evolve.