The right testing can make a significant difference in AML treatment, personalizing care for patients. Dr. Sangeetha Venugopal shares an overview of the essential tests performed following an AML diagnosis, how molecular testing helps to determine treatment options, and why repeat testing may be needed as the disease changes over time.
Dr. Sangeetha Venugopal is Assistant Professor in the Department of Internal Medicine and Division of Hematology at the University of Miami. Learn more about Dr. Venugopal.
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Transcript
Katherine Banwell:
Dr. Venugopal, what is personalized medicine, and how has this care approach affected how AML is managed today?
Dr. Sangeetha Venugopal:
I started my fellowship in 2017, and that jump-started the era of personalized medicine in acute myeloid leukemia because 2017 marks the approval of FLT3-targeted therapy, which is midostaurin (Rydapt). Since then, we have had several molecularly targeted therapies approved in AML. It is an exciting time to be practicing as a leukemia physician, mainly because we are targeting the specific mutations that constitute acute myeloid leukemia.
That said, acute myeloid leukemia is not a monoclonal disease, meaning it’s not driven by only one mutation. For example, chronic myeloid leukemia (CML) is driven by only BCR-ABL fusion, so our 9;22 translocation. We have one specific medication that targets that particular translocation. In fact, that has changed the outcomes of patients with CML dramatically. In this era, if a patient gets diagnosed with CML and they get treated, they have the same expected survival as someone without CML.
That, in my opinion, is fantastic. But in AML, although we have come far, leaps and bounds compared to several decades ago, we acknowledge our limitations in the sense that AML is a polyclonal disease, meaning it’s not only one player that drives the disease forward. It’s multiple mutations. For example, even though I say FLT3-targeted therapy has changed the paradigm of treatment, because it definitely has, this is reflected in classifications and risk prognostications as well. The 2017 AML risk classification lists FLT3 in the intermediate- to higher-risk. However, the following classifications put them in the intermediate-risk category. This happened because of this particular targeted therapy. I do think it’s a combination of both targeted and non-targeted therapies that will drive the field forward.
That said, personalized medicine is particularly important because some patients may have just one mutation. At each level of disease, it’s really important for us to get the genomic testing to understand what is driving this disease. It’s not only essential to get the genomic testing at diagnosis, but every time the disease changes its course, we need to get the genomic testing so that we can help the patient in a better way.
Katherine Banwell:
Dr. Venugopal, what key testing should people with AML have following a diagnosis?
Dr. Sangeetha Venugopal:
When I see my patient with a suspicion of newly diagnosed AML, I order a bone marrow biopsy because morphology is very important. Without morphology, we don’t move further. It has to have 20 percent blasts in most situations.
Then we ask for a karyotype, or cytogenetic analysis. As females, we have 46, XX. If someone is a male, they have to have 46, XY. That’s the normal chromosomal karyotype. However, when someone gets a disease like AML, the chromosomal structure changes. Those chromosomal changes are important. For example, KMT2A-rearrangement is a chromosomal translocation, and those play a major role in risk prognostication of AML. The next thing we look at is flow cytometry because we need to know what is the composition of the immunophenotype of AML at diagnosis because this is important. When the patient achieves the remission, we are looking at something called measurable residual disease. At that time, the flow cytometry is important for us to find out if they have the same phenotype or if there is nothing there and they are in deeper remission.
The other testing that we perform is next-generation sequencing. This is the one that I’m talking about in terms of personalized medicine, because the next-generation sequencing will pick out all the mutations that constitute the AML genome.
Katherine Banwell:
Dr. Venugopal, what is molecular testing, and how has it changed the way you treat AML?
Dr. Sangeetha Venugopal:
Molecular testing is – let me walk through a scenario. Say, for example, if I have a new patient with AML and I’m waiting for the molecular. In my institution, I get it within 72 hours. The 72 hours is key, because it’s really important for us to understand what drives the disease, and not necessarily to decide on the treatment. Well, I take it back. It is necessary to decide on the treatment—not from the get-go, because if I am putting my patient on a clinical trial or for molecularly targeted therapies, then I would need to know what is the beast I’m dealing with before I can tame it.
If the patient has, say, for example, FLT3-mutated AML, and I’m finding this through the next-generation sequencing, it’s important because I will be able to add a FLT3 inhibitor if the patient is someone who can receive intensive chemotherapy, and the FLT3 inhibitor is added on day 8.
If someone is older, there are clinical trials that will incorporate a FLT3 inhibitor in the frontline along with the hypomethylating agent and venetoclax (Venclexta), which will improve their outcomes in the newly diagnosed setting, as opposed to treating them with just FLT3 inhibitor monotherapy when the disease relapses.