AML Program Highlight: AML Biomarkers: How Testing Shapes Your Treatment Options

I sat down with The Patient Story’s patient advocate Steve Buechler and Dr. Strickland to discuss how AML biomarker testing shapes patients’ treatment options. Here are some of the key points of our discussion.

Steve Buechler: Dr. Strickland, what are biomarkers, and what are the different types? We hear about diagnostic, prognostic, predictive, monitoring — it sounds pretty complicated. Can you sort it out for us?

Dr. Stephen Strickland, MD: Historically, AML was diagnosed simply by looking at cells under a microscope. And we know now that those cells can look similar under the microscope, but the biology of AML is very heterogeneous. Looking at these biomarkers helps us understand the true diversity of the disease and helps us predict both prognosis and therapeutic options.

A lot of different biomarkers have been developed over the years. We now have a broader spectrum of testing that we do as standard of care at the time of diagnosis to guide our treatment decision-making.

Steve Buechler: For AML in particular, what biomarkers do you commonly test for?

Dr. Strickland: That’s a great question. There are different types of biomarkers, and what we’re really looking at is the biology of the leukemia cell. One major category we look at is cytogenetics — also called a karyotype — which is a chromosome analysis of the leukemia cells. These genetic changes can help us classify patients into favorable, intermediate, or high-risk categories. That classification can influence which therapies we consider, including whether to pursue a clinical trial from the beginning or look ahead to stem cell transplant if the patient achieves remission.

Historically, we’ve had cytogenetics for decades, but more recently, we’ve added molecular profiling using PCR-based tests, single-gene assays, and next-generation sequencing (NGS). These NGS panels can screen for anywhere from 35 to 200 mutations, giving us a vast amount of information.

Some mutations have become standard to test at diagnosis. For example:

• FLT3: Patients with FLT3-ITD mutations tend to have higher-risk disease, although the development of FLT3 inhibitors has improved outcomes.
• IDH1 and IDH2: These mutations have treatments now, historically used in the relapse/refractory setting, but data is emerging on using them in frontline therapy.
• NPM1: Initially important as a prognostic factor, it’s now also being considered as a therapeutic target, especially with new menin inhibitors.

We’ve seen exciting recent developments, including the approval of revumenib—the first therapy for patients with KMT2A-rearranged relapsed/refractory AML. This is being studied in combination with other therapies even in the frontline setting.

At the ASH 2024 annual meeting, data was presented on menin inhibitors like bleximenib and ziftomenib. Both showed promising results when combined with intensive induction chemotherapy, including high complete remission (CR) rates and MRD-negative CRs—which means deep remissions we can verify through molecular testing.

Importantly, these drugs also showed strong activity in patients with NPM1 mutations and KMT2A rearrangements—two groups that have historically responded poorly to standard chemotherapy. So we’re hopeful that this marks a real breakthrough in treating these harder-to-treat cases.

Steve Buechler: Do any of these biomarkers or mutations tend to cluster in specific groups of people based on age, gender, or other social factors?

Dr. Strickland:There’s a variety of factors that we can see. NPM1 can occur sort of across the age spectrum, if you will. But the other aspect is what mutations or other abnormalities are co-occurring, and that has influence. So NPM1 by itself is thought to be a favorable risk feature. But there’s also data that suggests NPM1 when it co-occurs with, say, an IDH mutation or a DNMT3A mutation, that it’s the positive impact may take a hit based on the co-occurrence of these other mutations. And for instance, when NPM1 co-occurs with a FLT3 mutation, FLT3 by itself puts patients into a high-risk category, so to speak. But FTL3 plus NPM1 puts them in an intermediate risk, whereas NPM1 patients by themselves go into a favorable risk.

So I think it’s really not just any single mutation that’s driving it, but really looking at the bigger picture of the molecular profile and the diversity even within a single patient’s leukemia to try and see what the impact is and open the door for additional therapies. We do know that the KMT2A rearrangement historically has been associated with patients who have seen prior anthracyclines, so part of this therapy-related leukemia that we were talking about earlier, some patients who receive prior anthracyclines will have a KMT2A rearrangement and that confers a higher risk disease. And so the availability of these therapies for a traditionally high risk patient population is going to be very important.

Steve Buechler: That makes sense. When I was treated back in 2016, I was given the standard 7+3 chemotherapy, and they tested only for FLT3 — which I didn’t have — and NPM1, which I also didn’t have. They said that would’ve been good to have. So I had neither and ended up in the intermediate-risk category, especially with a normal karyotype. At the time, I didn’t understand any of this — it’s a lot to take in. But thank you for that explanation. How and when do you test for these biomarkers?

Dr. Strickland: At the time of diagnosis. It’s critical to test early because it helps us understand prognosis and also informs treatment choices. Even if we have to start treatment immediately, we want to get these samples before therapy begins. That way, we have the necessary data to decide whether a stem cell transplant might be needed in first remission or whether a patient might benefit from a targeted therapy. We also retest in some cases during remission to evaluate measurable residual disease (MRD)—meaning whether there’s still any detectable leukemia at a very sensitive level.

Steve Buechler: And is this typically done through a bone marrow biopsy?

Dr. Strickland: Yes, usually at diagnosis, it’s done through a bone marrow biopsy, using the aspirate—the liquid part of the marrow.

But some of the tests can also be done from peripheral blood, especially for monitoring over time. There’s some debate over sensitivity between marrow and blood samples, but doing follow-ups through blood can help reduce how often patients have to undergo marrow biopsies. Those are not the most pleasant thing to repeat frequently.

Steve Buechler: Despite its importance, early biomarker testing still isn’t standard everywhere. Why is that, and what are the barriers?

Dr. Strickland: It’s improving, especially over the last several years, and it’s now recommended in the NCCN guidelines. But access still varies depending on where a patient presents.

If a bone marrow biopsy is done at an outside hospital that doesn’t have access to the full panel of molecular testing, we often have to repeat the biopsy once they arrive at a center like ours.

It’s not ideal, but it’s necessary to make informed treatment decisions.

It really takes a team effort—oncologists, pathologists, hospitals—to advocate for this testing and ensure it becomes routine practice.

Steve Buechler: How do biomarkers play a role in clinical trials? Can they make you either eligible or ineligible for certain trials? How do those two things work together? 

Dr. Strickland: Yeah, so, you know, it’s definitely been an evolution in the leukemia research space, the clinical trial space, and I’ll say oncology research in general space, and that, you know, as we mentioned earlier, we’re trying to take advantage of the biological characteristics of one patient’s tumor. And so there are a lot of studies that are being so-called biomarker-driven. And if a patient’s malignancy has a specific marker, then we’re trying to get them access to these targeted therapies or snipers, if you will, that we referenced earlier. And so I think that there are opportunities where, you know, sometimes these drugs may be more effective on a broader scale, but at least with the initial development, we’re also trying to enrich the population of patients who are truly gonna likely, hopefully, have a benefit from the medications. And so it’s just us trying to take advantage of the characteristics we now can better understand about one person’s leukemia. Characteristics that we didn’t know existed, say, you know, 30, 40 years ago, but now we have the technology to help us identify this and identify it relatively quickly, and that can be instrumental in guiding us to either commercially available therapies or for clinical trial participation, where there may not be something that’s already FDA approved to target that.

Steve Buechler: So how does knowing someone’s biomarkers impact their treatment choices? And that includes, do biomarkers give you some idea about potential side effects or potential effectiveness of treatments?

Dr. Strickland: The biomarkers can definitely help to guide the decisions on therapy. Not so much from a side effect profile, but more so from an efficacy perspective. You know, the way that I think about our traditional therapies are kind of like going to battle with a tank. Tanks can be very effective, but they’re not very specific. And so some of these newer therapies, these targeted therapies like FLT3 inhibitors, menin inhibitors, IDH inhibitors — all of these therapies are kind of like adding a sniper to the mix. And hopefully by going to battle with maybe both tanks and snipers, if you will, hopefully we can have a more effective outcome in the battle against this malignancy.

For the rest of this interview, watch our program replay ON DEMAND.

AML Biomarkers: How Testing Shapes Your Treatment Options

Hosted by The Patient Story Team

Learn how understanding what mutation you have, like NPM1, IDH, KMT2A, and FLT3 can shape treatment choices—and how patients can work with their doctors to explore every option, including clinical trials.

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