The Role of Molecular Testing in Diagnosing Acute Myeloid Leukemia

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EP: 1.The Role of Molecular Testing in Diagnosing Acute Myeloid Leukemia

EP: 2.When to Perform Molecular Testing in Relapsed AML

EP: 3.Barriers to Molecular Testing in AML

EP: 4.Treating Newly Diagnosed Acute Myeloid Leukemia

EP: 5.Treatment Options for a Young, Fit Patient Newly Diagnosed with AML

EP: 6.First-Line Treatment Options for NPM1-mutant AML

EP: 7.First-Line Treatment Options for AML With KMT2a Rearrangements

EP: 8.The Potential Role of Menin Inhibitors in the Front-Line Treatment of AML

EP: 9.Exploring Potential Combination Treatments for AML

EP: 10.Menin Inhibitors in the Second-Line Treatment of AML

EP: 11.The Role of Menin Inhibitors in the AML Treatment Armamentarium

EP: 12.Determining Which Patients Will Benefit the Most From Menin Inhibitor Treatment

EP: 13.The AML Treatment Horizon

EP: 14.Menin Inhibitors in Acute Myeloid Leukemia: An Overview of “Encouraging” Early Data

Transcript:

Naval G. Daver, MD: I’m your host, Dr Naval Daver, associate professor in the Department of Leukemia at The [University of Texas] MD Anderson Cancer Center in Houston … I have a great panel consisting of health care professionals who will be joining me today for this virtual discussion on acute myeloid leukemia (AML). I would like to invite my fellow panelists to introduce themselves. Dr Erba?

Harry P. Erba, MD, PhD: Hi, Naval. Hi, everybody. My name is Harry Erba. I’m a professor of medicine at Duke University and serve here as the director of the leukemia program.

Naval G. Daver, MD: Dr Dan Pollyea.

Daniel Pollyea, MD, MS: Thanks, Naval. It’s a great panel. I’m excited to be here with you. I’m Dan Pollyea. I’m a professor of medicine at the University of Colorado, where I direct the leukemia program.

Naval G. Daver, MD: And Dr Eunice Wang.

Eunice S. Wang, MD: Hello. Delighted to be here as always. My name is Dr Eunice Wang, the director of the leukemia and benign hematology services here at the Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Naval G. Daver, MD: So, with that, we will launch right into it. We’re first going to … talk about molecular and cytogenetic testing in [AML]. I think before we get into any treatments, that is probably the most important thing because that helps guide the treatment decisions both in the frontline setting as well as in relapse. As we all know, [AML] is the most common of acute leukemias. It’s still a difficult disease. The recent SEER [Surveillance, Epidemiology, and End Results] publication from 2022 shows that the overall survival for [patients with] newly diagnosed AML … is about 32%. So, it’s slowly nudged up from 27% to 32% in the [past] 4 or 5 years. But still, 32% is quite dismal. Now there are differences in what we call fitter, younger, suitable for chemotherapy—different terminologies are being used.

But those who can have nonadverse cytogenetic and molecular testing, receiving intensive induction regimens, could have good survival, as close to 55% to 65%, depending on their underlying cytogenetics and molecular [data]. On the other hand, those who are having adverse cytogenetics, TP53, inversion 3 MLL [mixed lineage leukemia], other bad-risk features, and those who are older than 70, 75 [years] where it’s very difficult to deliver intensive chemotherapy, often have 5-year survival of 20% or less. [I]t is very important to know that there’s still a lot to be done in the AML space and then especially talking about relapsed AML, aside from FLT3 mutated, IDH1, IDH2 mutated, where we have targeted therapies and potentially combinations of targeted therapies showing good activity and maybe we can take the patient to transplant with some curative chance. The rest of the population remains difficult. So, starting with that, I’m going to turn it over here to Dr Eunice Wang to … talk through how she approaches the molecular cytogenetic testing for a [patient with] newly diagnosed AML in her institute at Roswell Park. Eunice.

Eunice S. Wang, MD: Thank you very much, Naval. So, at our institute, we perform what we would consider a comprehensive diagnostic work-up for patients [whom] we suspect [of having] newly diagnosed [AML]. Now, this differs from in the past when we were making a diagnosis of acute leukemia. We really looked for the presence of 20% or more blast in the peripheral blood or the bone marrow and then we would determine whether the patient, as Dr Daver mentioned, was fit for chemo[therapy] and we would start intensive chemotherapy within ideally 24 or 48 hours. We’ve recently learned that with the advances in targeted therapy over the [past] 5 years that it is important and potentially even essential for most patients to wait for the diagnostic and cytogenetic work-up prior to selecting treatment for our patients.

And that is a paradigm change for many of us trained in the age [when] acute leukemia was an absolute oncological emergency and needed to be dealt with immediately. At our center, we obtain the diagnosis of AML through morphology and flow cytometry, probably within 24 hours of a patient presentation. But we then wait for the cytogenetic results as well as, importantly, the mutational results before selecting therapy. And that’s because of the prognostic as well as therapeutic implications. The new European LeukemiaNet 2022 criteria continue to build upon prior classification systems in defining mutations, which are of adverse and intermediate particular risk. For example, we all think that testing for FLT3-ITD and -TKD by polymerase chain reaction [PCR] [testing] and next-gen[eration] sequencing is essential for addition of an FLT3 inhibitor to up-front therapy. We are increasingly looking at IDH1 to determine whether ivosidenib should be incorporated, particularly for older patients in combination with a hypomethylating agent [HMA]. And for many patients, we also look for the presence of NPM1, KMT2A rearrangements, normal vs abnormal cytogenetics, and now secondary mutations [that] place patients again in that adverse care category.

Our full molecular mutational profile takes a week or more. And there [are] data from a randomized retrospective study in Germany that [show] waiting that additional time,a week or two, in patients [who] are stable, particularly in older patients, is worth it. We have results from Beat AML [NCT03013998] and other trials, which my colleagues can speak to, which really demonstrate the superiority and potential treatment outcomes in getting that information, so we can integrate targeted therapies into prognosis. Lastly, we also look for those cytogenetic and mutational markers to determine prognosis and whether patients should go on to a subsequent allogeneic stem cell transplantation when they achieve remission vs continuing with chemo[therapy] alone. I [would] like to turn to some of my colleagues to see whether their institutes also do that or what their thoughts are on the work-up.

Naval G. Daver, MD: Let me ask Dr Pollyea … So, Dan, let’s say [a] young, relatively fit patient [is] coming to you, [aged 40 years]. What would be the molecular cytogenetic testing you’re going to send off and … what are you going to wait for vs it’s OK, I can start and then this can come later?

Daniel Pollyea, MD, MS: Right. Thanks, Naval … [I]n that situation, we would be looking to provide intensive induction chemotherapy to such a patient, a … healthy patient [aged 40 years with a new diagnosis]. And so, what we’re going to want to wait for, the information we need before we start treatment, is to understand [whether] they have a core binding factor AML. And if they do, then it’s our practice to give induction chemotherapy with gemtuzumab starting with day 1, following one of the large European groups. If possible, and it usually is like Dr Wang said, [we] wait before starting therapy to get that information. And then the other piece of information that doesn’t necessarily need to be acquired at the start of treatment but is necessary soon thereafter is to understand [whether] the patient has an FLT3-ITD or -TKD mutation because if so, then they would need to start midostaurin by day 8 of intensive induction chemotherapy.

So those are what we look for and wait for now. I think going forward in the future, there may be additional consideration to understand [whether] a patient has traditional adverse risk features that would portend a poor outcome with intensive induction chemotherapy and consider another therapy, perhaps a venetoclax-based therapy, for such a patient, even if they were a good candidate for a standard intensive induction chemotherapy regimen. I’m not sure that that strategy is quite ready for prime time or something that I would necessarily advocate waiting before starting treatment in an otherwise eligible patient for intensive induction chemotherapy. But if I had to predict the future, I would say that that’s likely where things are going to land.

Naval G. Daver, MD: Thanks a lot, Dr Pollyea. Let me ask you one more question. What about IDH in a young, fit patient? Any utility for treatment decision-making up front or transplant? How do you use that?

Daniel Pollyea, MD, MS: For us, that wouldn’t [affect] the up-front treatment decision. There are some compelling single-arm studies of induction chemotherapy with IDH inhibitors. And it’s possible that at some point that information might be necessary to add an IDH inhibitor in the up-front setting. But now, I don’t believe that the data support that. And so, we don’t wait for that information. And so, like Dr Wang was saying, there’s some molecular information that we need yesterday. We need it to make a treatment decision and we are going to make sure to prioritize that with our pathology laboratory colleagues. Other information takes longer. And [although] we could make workflows that would hasten those results, the turnaround time, something like IDH in an induction-eligible patient [with a new diagnosis], for us, is not information that we absolutely need. So that’s part of our large sequencing panel that every patient with a myeloid malignancy gets. But the turnaround time for that is 10 days to 2 weeks. So, we’ll know the IDH status, but we don’t need to wait for that to start treatment, in our view. And … that kind of information is important, not just IDH, but other elements of the patient’s disease biology that will help us make decisions on what do we do after the patient’s in remission. How do we cure them, and is that path going to take us to a transplant or not? And that’s how we make that decision with the information that will trickle back over the coming 2, 3 weeks.

Transcript is edited for clarity and readability.