From Lab to Life

Dr. Courtney DiNardo (00:00.218)
Hello and welcome to our program titled Mastering the Complexity of AML Treatment, a multi -dimensional approach to diagnosis, therapy, and side effect management.

Dr. Courtney DiNardo (00:12.674)
I'm Dr. Courtney DiNardo, Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center. Disclosures are displayed on the screen. And this educational activity is supported by independent educational grants from AbbVie and Estelle.

Dr. Courtney DiNardo (00:28.654)
So I think it's really kind of exciting how much things have changed in AML in the past, gosh, 10 years or so with 12 new approvals for different AML patient populations. But it also kind of makes it a little bit more challenging, of course, to try to figure out what the right treatment is for the right patient at the right time. So just thinking through the diagnosis of an AML patient, a lot of this is kind of what you had been talking about also.

One of the most important things is just recognizing that we wanna get the information back about the patient's leukemia as quickly as we can, because we don't wanna sit for weeks and weeks before we start treatment. course, AML is often a cancer where we really wanna start treatment in a timely fashion. So when we're talking about kind of diagnosis, the first thing of course is the morphology. So when a patient is presenting, we're doing a bone marrow, we're looking for elevated.

blast of the myeloid lineage, right? If they're the lymphoid lineage, they're ALL. So an AML, which generally is defined as greater than 20 % blast, but can be less than 20 % blast if there's an AML defining genetic abnormality. So certain fusion transcripts, for example, like the core binding factor leukemias, even if it's less than 20 % blast, that still defines a patient with AML.

And then we're looking at different kind of CD antigens on the surface that are standard for patients with different myeloid leukemias. And it helps kind of in that, the kind of old fashioned FAB classification, but it's still useful. And then what is particularly impactful now is kind of the cytogenetics and the molecular abnormality. know, things like standard routine cytogenetics, you talked a lot about that, that helps us identify patients with.

complex cytogenetics that are in that adverse risk group, patients with core binding factor leukemias that are in the favorable risk group. But there are multiple different somatic mutations that are recurrently mutated in our patients with AML. And these are really important to know. And I think it used to take us on average like three to four weeks to get these type of panels back and it's becoming faster. So for instance, in academic centers like

Dr. Courtney DiNardo (02:45.59)
like we have access to it often is only taking like three to five days, whereas send out places it's still more like two to three weeks. And so definitely, the sooner we get this information back, the more helpful it is to put treatment plans in place. One thing that's also kind of helpful to do is to assess for the possibility of extramedullary disease. It's not as common in patients with AML to have.

kind of foci of leukemia outside of the bone marrow and the circulation, but it certainly can happen in like 15 to 20 % or so of patients. And so that's something to be aware of often when the white count is elevated above like 50 ,000 or especially if a patient happens to have like a flip three mutation or an elevated LBH, they may have an increased risk of having CNS involvement. So thinking about an LP or a evaluation for extra medullary disease is important.

We can get some of the genomic information off of the peripheral blood. So that's something that can be done in patients who have circulating leukemia, but often at diagnosis, you know, we're really wanting the bone marrow because we want to see morphology. We want to know cellularity. There's a lot of kind of pieces of information that are essential in that bone marrow, at least for diagnosis. And then, you know, and then what is the goal of treatment? Well, of course, the goal of treatment is to, you know, first get the patient into what we call a remission.

and then hopefully a long -term remission leading to a cure. And so what do we mean by remission? know, remission is there's many different types of remission according to our classifications. A complete remission is kind of the gold standard, and that means that they have less than 5 % blasts in the bone marrow. They are no longer requiring transfusions. Their neutrophil count has recovered. Their platelet count has recovered. So a neutrophil count above 1 ,000, platelets above 100 ,000.

and a complete remission that doesn't have full count recovery can be called a CR with partial hematologic recovery. That's called a CRH. And that's if they have a neutrophil count above 500 and a platelet count above 50, they haven't met that true full CR criteria. Or we also have a CR with incomplete hematologic recovery. That's called a CRI. And that's when you have all the criteria of a complete remission.

Dr. Courtney DiNardo (05:02.312)
either the neutrophil count is not recovered or the platelet count isn't recovered. So those are kind of just different kind of nuances of our different CR criteria with a true CR being full count recovery of all the lineages. If you don't have any count recovery but you still have no evidence of leukemia in an informational bone marrow, meaning that there is cellularity there, you don't see any leukemia, but the counts haven't recovered, that's called a morphologic leukemia free state. And a partial remission, which we don't see that often

in leukemia, but it exists and rarely you'll see it maybe with differentiating therapy as patients are kind of slowly differentiating where you'll see full normal count recovery, the true CR count recovery criteria, but still some leukemia blasts there somewhere between five to 25 % and less than 50 % from when they started. So those are kind of the definitions of remission. And then, you know, that is.

kind of what we used for years and years, but I think more and more we're realizing the importance of something called MRD or measurable residual disease. So a patient with a complete remission, a CR can have either a CR that's MRD positive or MRD negative. And an MRD status is really just, it's a better estimate of residual disease because even if you have less than 5 % blast, maybe 1 to 2 % of those blasts are leukemia.

or maybe they're normal. So just getting to a deeper sense of, you know, below the limits of morphology, what our pathologists are seeing, is there still leukemia there that we can detect with fancier assays? And we know through following both patients receiving intensive chemotherapy and with lower intensity therapy, that having persistent MRD is associated with shorter remissions and a higher chance of relapse. And so that's.

kind of it is an increasingly important endpoint that we are paying a lot of attention to because, you we know if a patient is still MRD positive and they've completed maybe their induction consolidation therapy, they're probably going to relapse because there's still leukemia that we can detect. And so there's different ways that we can detect MRD. The two most commonly used, one is called PCR.

Dr. Courtney DiNardo (07:18.958)
QPCR or RTPCR, this is a very standardized and highly sensitive way of looking at residual disease, but you have to have kind of a specific genetic abnormality to PCR. And so that's about 50%, 40 to 50 % of our AML patients. And that's a fusion transcript, a core binding factor leukemia, NPM1 mutations can be perfect for PCR analytics. so PCR is the most sensitive and the most standardized

if available for your patient with AML. Across the board, we can do something called flow cytometry or multi -parameter flow cytometry. is actually, it comes back faster. It can be resulted in only like a day or two, but it's a little bit more challenging for pathologists. There's a bit of a learning curve. And so it's difficult to standardize with a lot of kind of user interpretation.

but it is relevant and applicable for all patients with AML. Often, we will do flow cytometry for everyone and then PCR in patients where that is available. It is complementary and studies have shown that doing both can be complementary. There is also increasing interest and validation of using next -generation sequencing or NGS for MRD.

that's not yet standardized. It allows you to check kind of the different mutations in that patient, you know, in the setting of remission, have those mutations disappeared or can you still detect them? It's a little bit challenging because, you you talked about clonal hematopoiesis. There are patients who have CHIP clones or like pre -leukemia mutations like DNMT3A, TAT2, ASXL1. If those are still persistent in remission, does that mean it's MRD or is that just a pre -leukemic clone?

So some of those types of nuances are important when you're thinking about NGS, and that's some of why it's not yet fully standardized. But you can do MRD testing in either peripheral blood or bone marrow. Bone marrow is of course a bit more sensitive, but both are appropriate. And we now have guidelines, primarily from the NCCN and ELN criteria, telling us that in patients with

Dr. Courtney DiNardo (09:34.232)
kind of core binding factor leukemia, NPM1, these mutations that are associated with favorable risk leukemia, you know, we should be monitoring. And if we're still seeing persistent MRD after two cycles of therapy, that actually indicates that a patient who wouldn't otherwise go to transplant may actually benefit from a transplant because they have such a high risk of relapsing. So these are really important for us and are changing the way we think about kind of classification and treatment decisions, not just a diagnosis, but also as time goes on during therapy.

So then in terms of kind of treatment, so the big question about how are we going to decide what treatment to do for our patients? I think we all trained in the world of kind of two different options, right? It was seven and three for patients who were fit for intensive chemo, and then like azacytidine, decytidine, or lotoseracy for people who were not kind of appropriate or fit for intensive chemotherapy. And that's definitely changed.

We still think about patients who are kind of fit for intensive chemotherapy, but if you're fit and appropriate for intensive chemotherapy, we're thinking, are you favorable risk? Because if you're favorable risk with the core binding factor leukemia, we know we want to add gemtuzumab to your chemotherapy. Do you have a flip three mutation? Because if you do, then we want to add a flip three inhibitor, either mitastorin or quizartinib or approved in the frontline setting. Do you have a therapy related MDS?

therapy -related leukemia or AML from a prior MDS or antecedent hematologic disorder. you do, then liposomal 7 and 3 is approved and has shown benefit in that patient population. All of these are important. We want to know this information before we start treatment because it really impacts what we're doing. Then patients who are going to transplant, that tends to be all the adverse risk patients appropriate for transplant intermediate patients who

you think are benefit, that's more of a risk benefit discussion or favorable risk patients who remain MRD positive. We're thinking about transplant and if we're not thinking about transplant, that's where oral azacytidine is approved and a great option to improve relapse free survival and overall survival in young patients getting intensive chemo, not going to transplant. Then for our patients who are not appropriate for intensive chemotherapy, that's where we've had really quite a

Dr. Courtney DiNardo (11:52.696)
quite a shift with the addition of Venetoclax to Azacytidine or Decidabine or Lodocerosate. It's approved with all of those three backbones and has improved survival and is, I think, really kind of a key update for and availability for our older patients with AML. But also, you know, this is where

Mutational testing for IDH1 is really important because if you have an IDH1 mutation at diagnosis, the approval of azosididine and Ivosidinib is approved with phenomenal increased survival rates compared to azosididine alone with good tolerability. Relapse patients, this is where we need to know, do you have an IDH1? Do you have an IDH2? Do you have a FLIT3 ITD, a FLIT3 TKD mutation? Because we have targeted therapies for all of these.

And it's also important to realize that, you just because you had a flip three mutation, a diagnosis, for instance, it's not always going to be there at relapse because clones can shift and therapy can change the type of leukemia. So kind of doing mutational testing at different time points is really critical. So you're using kind of the best treatment for that patient. So.

key principles that help guide treatment decisions. I think there's kind of a number of them, but just to highlight some of them is realizing that relapsed refractory AML is unfortunately a primary cause of mortality. That age is not the sole determinant for therapy intensity. And just because a patient is maybe younger, but they have certain comorbidities, maybe we should be thinking about lower intensity combinations or vice versa. An older patient who's very fit may benefit.

especially if they have a core binding factor leukemia and we know they could be cured with intensive chemotherapy. That's why evaluation of comorbidities is really important. Geriatric assessments can be incredibly helpful to provide treatment and prognostic insights. It's really important to talk about goals of care early. Talk to your patients, what's important to them to know how to best.

Dr. Courtney DiNardo (13:58.424)
treat the patient in front of you, know the kind of desires of that patient. And that's really, you know, of course important to make sure that we're all working together and making sure we have the same kind of goals and endpoints. Transplant is really important. We got to think about, you know, transplant early for all of our patients, really, regardless of what therapy they're getting, you know, are we thinking about a consolidated transplant? If we are, let's get transplant involved quickly. Let's get that, you know, let's figure out who the right donor is and kind of get that process started.

And remembering again that response to therapy is dependent on kind of the genetics. so genetics is really important for defining the best treatment approach and the anticipated outcomes. So in summary, we can test for MRD with qPCR, with flow cytometry, with NGS. Each method has advantages and disadvantages. And in the future, I suspect we'll be using many of them at the same time.

It's most beneficial when it's measured sequentially. So it's not just a one -time MRD, yes, no, you're monitoring your patient over time during and after induction therapy, before transplant, at other treatment -specific times. And remember that the 2024 NCCM AML guidelines recommend specific therapies based on cellular molecular cytogenetic biomarkers. Well, that's all the time we have for today. We would also like to thank Avvy and Estellas for their support of this program.

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