INSIST! on Better Care: Why AML Testing Matters

Katherine Banwell:

Hello, and welcome. I’m your host, Katherine Banwell. Today’s program is part of the Patient Empowerment Network’s Insist series.

We’ll hear directly from an expert on how key testing can impact AML care and treatment options.

Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you. Well, let’s meet today’s guest. Joining us is Dr. Anand Patel. Dr. Patel, welcome. Would you please introduce yourself?

Dr. Anand Patel:

Yeah. Thanks so much for having me. So, I’m Anand Patel. I am an assistant professor of medicine at the University of Chicago, where I focus on taking care of patients with acute leukemias, chronic leukemias, and myeloid cancer. So, cancers that are at risk of developing into acute leukemia. I serve on the NCCN panel for acute myeloid leukemia, and then, also, for myeloproliferative neoplasms, and I’m the medical director of our inpatient leukemia service. So, very happy to be here today.

Katherine Banwell:

Well, thanks so much for taking the time out of your day to join us, Dr. Patel. I’d like to start by defining what AML is for our audience.

Dr. Anand Patel:

Yeah, absolutely. So, AML is, broadly speaking, a blood cancer. And when we think about blood cancers, when we think about blood cells, and as they kind of grow up from being stem cells into their kind of more adult roles, they can become either myeloid cells or lymphoid cells.

Acute myeloid leukemia is a myeloid cancer, and really, what it’s defined by is having increased numbers of very immature cells called blast cells, and specifically, myeloblasts. When you think about a bone marrow, its typical job is to make healthy blood cells. So, if the bone marrow is making too many of these immature cells or blast cells, that can lead to crowding out of the healthy blood cells that should be made, which can then have medical issues or concerns, such as anemia, low hemoglobin, risk of infection, or thrombocytopenia, low platelets, which can put someone at risk of bleeding.

Katherine Banwell: 

As I mentioned, we’re going to focus today on how test results can impact care. Would you explain why testing is so critical in AML?

Dr. Anand Patel: 

So, many cancers, including AML, have specific mutations that develop over the course of time that serve as the driver of this. These mutations can have prognostic impact. So, give us a sense of how likely standard therapies are able to work, whether something like a stem cell transplant may be needed to try and cure this, and they can offer therapeutic information.

So, we have several drugs that fall in a bucket of what we call targeted therapies. So, they are very precisely developed for patients that have a specific mutation. In tandem with molecular testing, getting what we call cytogenetic testing. So, looking at the makeup of the chromosomes in these leukemia cells. So, chromosomes being the packets of genetic information. Missing chromosomes, chromosomes rearranged in specific ways, those also help to refine both our prognostic discussion, so, getting a sense of how likely the leukemia is to respond to therapies, and therapeutic decision-making.

Katherine Banwell: 

Before we get into treatment, would you go over the key tests that patients can expect with diagnosis? And you did mention a couple, but maybe we could start with blood tests?

Dr. Anand Patel: 

Absolutely. So, for most patients who ultimately are diagnosed with AML, their journey begins with blood work, and typically, what’s called a complete blood count with differential.

So, a complete blood count looks at the different components, most specifically the white blood cell count, the hemoglobin, or red blood cell count, and the platelet count. And then, a differential is someone looking at the white blood cells under a microscope and defining what different types of white blood cells are there. For many patients, what may be found is their white blood cell count is much higher than expected, or much lower than expected, they may have a low platelet count or hemoglobin count, and as that differential is run, there may be abnormal cells or blast cells that are seen in the blood.

Oftentimes, the next step, then, is to perform what’s called a bone marrow biopsy, which is an outpatient procedure. It is typically a bedside procedure, and the entire procedure itself takes maybe about 15 to 20 minutes, with some laying flat afterwards. On that bone marrow biopsy specimen, typically, what’s sent for is what we call a hematopathology review.

So, a pathologiwst who has expertise in reviewing bone marrow biopsy specimens, and other kind of blood cancer associated specimens, will review these specimens under the microscope. In addition, from that bone marrow biopsy specimen, we typically will send what’s called flow cytometry. So, looking at specific markers that may be seen on the leukemia cells. We will send molecular testing, so, looking for the genetic abnormalities that may be present in these leukemia cells. And we will send cytogenetic testing.

Typically, the cytogenetic testing can be done via what’s called karyotyping. So, looking at chromosomes under a microscope, and looking if big chunks of them are missing or swapped around. There’s also what we call FISH testing, which can look for more precise chromosomal abnormalities. But you have to know exactly what FISH abnormalities you’re looking for, because you have to pick what probes are sent to specifically evaluate for those abnormalities.

And in summary, those tests, typically, are what are necessary to arrive at a diagnosis of AML and also assign a risk stratification to someone’s AML.

Katherine Banwell: 

Are there questions that patients should ask about their diagnosis?

Dr. Anand Patel: 

In my mind, when I meet a patient for the first time, the things that I want to make sure I review with the patient, and oftentimes, these will encompass many of the questions that come up, is, “What is my diagnosis? What are these symptoms or complications that I can expect with this diagnosis? What is my risk stratification?” So, not just what my diagnosis is, but do I fall in a favorable or a less favorable risk category? I think it’s always important to talk about what would things look like if, for one reason or another, this was not treated at all.

I think it’s always important to have that perspective of, “What would happen if someone chose to not receive treatment for their AML?” And then, I pause there and see what additional questions may come up before we move into treatment, and what that may look like.

So, from a treatment perspective, I think the important things for patients to consider is, “What are the standard approaches for my AML? What is the expected rate of success or remission for my AML? Are there clinical trials that are available to me that would be considered? What would be the potential benefits and drawbacks to participating in a clinical trial, versus the standard treatment? And ultimately, what would be the expected side effects of the treatment itself?” Where treatment needs to be delivered.

So, whether it can be delivered at a center closer to home, versus at a maybe further away center with more expertise in AML. “Does the treatment need to be delivered in the hospital, or can it be given in the clinic? And then, is there a route to cure for my disease?” So, will that route to cure involve chemotherapy alone? Would something like a stem cell transplant be considered? Or are there features that let us know, even from the beginning, that unfortunately, there may not be a way to cure this disease, but rather, our goal is to try and maintain control for some amount of time?

Katherine Banwell: 

Unlike other cancer types, AML is not staged. It’s categorized by risk, and you touched upon this a few moments ago. How would you define low-risk and high-risk AML?

Dr. Anand Patel: 

Great question. Really, what we utilize is the prognostic risk stratification tools, which, again, are informed by the genetic and chromosome abnormalities that are seen in the AML cells. Interestingly, how high or low someone’s white blood cell count is, in general, does not influence your prognostic risk stratification for AML. And as I mentioned a bit earlier, the risk stratification tool that should be used is actually somewhat informed by what treatment you may recommend.

So, we know that these risk scores are not one size fit all. They are developed based on the therapies that someone is likely to receive. So, in patients that receive intensive chemotherapy for their AML, we use the ELN22 risk score, and their patients fall into these buckets of favorable risk, intermediate risk, or adverse risk.

The way I generally describe favorable risk AML is that the goal is to try and cure the leukemia with chemotherapy alone. Many patients can achieve that goal and do not need a stem cell transplant.

For intermediate and adverse risk AML, in general, the goal is to use chemotherapy to achieve a remission, and then for appropriate patients to try and then proceed with a stem cell transplant with the goal of cure.

Adverse risk AML, in particular, has a high risk of coming back even after a stem cell transplant is done. So, that is something that’s very important to discuss.

But ultimately, instead of staging, we really rely upon these risk stratification tools.

Katherine Banwell: 

We’ve alluded to the fact that test results impact treatment choices. Would you define induction and consolidation therapy for our audience?

Dr. Anand Patel: 

Absolutely So, induction and consolidation is terminology that is typically utilized for patients that ultimately receive what we would call intensive or high-dose chemotherapy.

Induction chemotherapy is the first kind of high-dose or intensive regimen that a patient receives, and the goal of that is to put the disease into a remission. Meaning, when we look for leukemia again with a bone marrow biopsy, we see that these blast cells have been reduced to under 5 percent, which is typically what defines a remission.

After induction, there may be anywhere from one to four additional rounds of chemotherapy that we refer to as consolidation. So, the goal there is to maintain the remission and to try and convert that remission into a cure. Now, for patients with favorable risk AML, again, the goal is to use induction and several cycles of consolidation to achieve a cure.

For those with intermediate and adverse risk AML, typically, we are looking for induction to put the disease in a remission, and for consolidation to maintain that remission, while the appropriate workup is being done and considerations are being made for a stem cell transplant. But this kind of terminology of induction and consolidation largely applies to the intensive chemotherapy approaches that we use for AML.

Katherine Banwell: 

That’s good information to have, Dr. Patel. I’d like to get into the impact of test results. How do they influence treatment decisions?

Dr. Anand Patel: 

So, we are living in a very dynamic time for AML treatment. So, for over 50 years, kind of the de facto standard treatment for AML was using induction chemotherapy, a regimen that we commonly refer to as 7+3, for anyone who was fit enough or well enough to receive intensive chemotherapy.

For patients who would potentially stand to be harmed more than benefited by intensive chemotherapy, they were either supported with transfusions alone or treated with a class of drugs called hypomethylating agents, mainly as a means of disease stabilization.

However, nowadays, we have a lower-intensity approach, this azacitidine (Vidaza) plus venetoclax (Venclexta) approach, where the remission rates approximate, and in some instances, could be slightly better than intensive chemotherapy, with less of a side effect burden.

So, it’s really a nuanced discussion about which treatment option should be used initially, and risk stratification plays a huge role in that nuanced discussion.

Now, an example I will use is, for patients who are well enough to receive intensive chemotherapy and that have what we call favorable risk AML, with the risk models that we use for intensive chemotherapy, they really stand to benefit from receiving that intensive chemotherapy because the goal is cure.

On the other hand, for many patients who have intermediate or adverse risk AML, they could potentially receive intensive chemotherapy with the end goal being a transplant to try and cure the disease, or they could receive this lower-intensity regimen of azacitidine, venetoclax, which is just as likely, and perhaps slightly more likely, to induce what we call a remission, and then subsequently receive a stem cell transplant, if needed.

The major thing to consider with lower-intensity therapy in patients who may not be able to proceed with a stem cell transplant is typically, they are considered indefinite therapies. So, as long as they are working, we keep delivering cycles at a frequency of anywhere from four weeks, to up to even eight to 10 weeks between cycles. Whereas with intensive chemotherapy, typically, patients will receive that induction regimen, followed by one to four cycles of this consolidation regimen, and typically, are then observed afterwards.

Katherine Banwell: 

We know that testing goes beyond diagnosis. Can you explain measurable residual disease, or MRD?

Dr. Anand Patel: 

Yeah. So, MRD is an incredibly important tool. The best analogy I like to use for measurable residual disease, or MRD, is an iceberg. You only know how deep the iceberg goes underneath water if you’re going down deep enough to look, and MRD is kind of that.

So, when we think about leukemia, if you look under a microscope, a really, really good hematopathologist can pick up maybe one in 100 leukemia cells. You, then, can add additional tests to kind of interrogate whether disease is there or not more deeply.

For example, patients who have these FISH abnormalities in their chromosomes that we can detect with FISH testing, you may be able to pick up one in 400 to one in 600 abnormalities when you incorporate what’s called flow cytometry. So, looking at the markers, the abnormal markers seen on leukemia cells, that can then pick up anywhere from, say, one in 2,000 to one in 10,000.

And then, you have what are called molecular MRD markers. So, there are some molecular abnormalities. Two good examples are NPM1 and FLT3, where, depending on the testing done, you can even pick up one in 100,000 leukemia cells. So, we’ve kind of gone beyond just looking under the microscope and saying the disease is not there, at least under the microscope.

We also will complement that with whatever MRD test is most appropriate for the patient, based on their disease characteristics at diagnosis.

Katherine Banwell: 

Well, and that’s really my next question, is, how does MRD influence the next steps?

Dr. Anand Patel: 

So, we know that any detectable leukemia is something we don’t want to see. And patients, for example, that are in a favorable risk disease bucket at diagnosis, if after they receive up to two cycles of chemotherapy, intensive chemotherapy, for example, we’re seeing that their disease is still present at a very low level. That may change our decision-making around the right the route to cure. We may start thinking, “Well, we know that this was a favorable risk leukemia when we kind of learned everything about it at diagnosis. But now, based on the fact that there is MRD that is not going away, we may need to think about something like stem cell transplant to try and cure this disease definitively.

Other ways this decision-making can be influenced is, do we need to intensify the therapy that we are giving to try and eradicate or get rid of that MRD? MRD not only influences decision-making about transplant or not; it can also influence decision-making about what might need to be done in someone who ultimately receives a stem cell transplant to keep the disease in a remission, what we call maintenance therapy. And the concept of maintenance therapy can also be applied in patients who don’t ultimately go into a transplant.

So, we’re not going to keep giving you the same sort of chemotherapy you’ve received up until this point. But we know that we have to administer some sort of treatment, whether it’s an oral pill or otherwise, to keep the disease in a remission. Because if we do nothing, this very, very low amount of disease may become significant disease again.

Katherine Banwell: 

Well, could you walk us through how test results might change a patient’s treatment options over time?

Dr. Anand Patel: 

Yeah. So, in my mind, you can think about what someone’s leukemia is at diagnosis, which we’ve discussed. Really kind of looking at the genetic and the chromosomal makeup to allocate risk, and the treatment decisions that are made based on that, at additional diagnosis. You can then think about testing once someone is in a remission, which is where measurable residual disease comes into play. So, not all remissions are created equal. Depth of remission matters.

So, patients that are MRD-negative, using our most sensitive testing, that gives us more confidence that this is a remission that will hopefully be durable, and ultimately be a cure. On the other hand, those patients who still have low levels of disease, we think about, how do we intensify therapy, or think more strongly about a stem cell transplant?

And then the third major time point at which testing is so critical is in this scenario where either someone’s leukemia never went into a remission in the first place, or it went into a remission and then returns. So, what we call a relapse of disease. And leukemia, unfortunately, is not static. Just because someone had a specific mutation in their leukemia cells when they were first diagnosed does not mean those same mutations are what will be there if the disease persists or if it comes back.

So, repeat molecular and cytogenetic testing at time of progression or relapse is critical. Especially because in the relapsed setting, where the disease has gone away and then come back, we have several therapeutic options that rely upon specific mutations being present.

Katherine Banwell: 

Dr. Patel, could you define for us targeted therapy, and who it might be right for?

Dr. Anand Patel: 

So, targeted therapy, in my mind, is any therapy that leverages abnormalities seen within someone’s cancer cells and can kind of leverage those abnormalities as a as a target.

So, a good example is patients who have a mutation in IDH1, that have AML. We have two drugs that are specifically effective in those patients. There’s one called ivosidenib (Tibsovo) and one called olutasidenib (Rezlidhia). Those drugs have been studied and have shown benefit because they specifically act on that IDH1 abnormality.

Now, by that same token, if we were to try and use those drugs in someone that did not have an IDH1 mutation, they are very unlikely to work. And that, I think, is targeted therapy in a nutshell. A precise way to target the abnormalities in someone’s leukemia cells or cancer cells, recognizing that because you’re targeting those abnormalities, not all patients would benefit from this, particularly if they don’t have that target.

Katherine Banwell: 

Do all hospitals provide mutation testing for AML? And if not, how can patients insist on additional testing?

Dr. Anand Patel: 

So, there’s been a lot of work to go into underscore the absolute need to do molecular testing or genetic testing. Not just at diagnosis, but at these various time points we’ve discussed. So, at time of remission, and also if the disease were to come back or to persist. This has been incorporated into all major guidelines for AML. So, an example is, I am part of the National Comprehensive Cancer Network AML guidelines, the NCCN guidelines. And in an effort to make sure that this testing is not only being offered, but done, we’ve incorporated that testing into the guidelines.

And this has been done in various other kind of AML authoritative recommendations. I say, as a patient, you should feel empowered to specifically ask, when you are undergoing that bone marrow biopsy, “Will this be sent for molecular testing? Could you tell me the name of the panel that is being sent?” Because the amount of genes that are looked at can actually vary widely depending on the panel that is sent. And if the answer is “No,” or “I don’t know,” I think patients should feel incredibly empowered to push for it, because it is the standard of care.

Molecular testing influences so much of our decision-making around AML. If you don’t have molecular testing, it’s a little bit like driving with an outdated map. You kind of sort of know where you’re going, but you certainly would love to have the GPS on top of that.

Katherine Banwell: 

Dr. Patel, we know how important it is for patients to speak up and advocate for themselves. If something doesn’t feel right, whether it’s side effects, the treatment plan, communication, or lack of, what should patients do?

Dr. Anand Patel: 

I don’t want to speak for all of my AML-treating colleagues out there. But I would say, at least for my colleagues at the University of Chicago, we very much communicate. We would much rather hear about something and be able to reassure a patient, than not hear about it, and then find out that they needed to go to the ER or got sicker.

So, in my mind, overcommunication, rather than under-communication, is key. Early communication of symptoms is essential, because for a lot of the symptoms that may pop up, for example, nausea, we kind of have a standard anti-nausea regimen, but there are various levels that we can step up to, if needed. We can add more of these, what we call “as-needed medicines.” We can come across a more standardized anti-nausea scheduled regimen. So, taking these medicines on more of a daily or couple times a day basis, if the nausea is prevalent. But we can only do that if we know that these symptoms are happening.

The other kind of alarm bell symptom that we always want to hear about is fevers in our patients with AML. So, a fever is almost always a medical emergency, meaning antibiotics need to be initiated, patients need to go to their closest ER, be observed in the hospital, if they’re having high fevers while undergoing AML treatment.

In that same way, we can only know to pass on that kind of advice if we hear about someone having a fever at home. And the other example I’ll mention is mucositis, or rawness of the mouth. Oftentimes, patients feel like they have to kind of just deal with it, but we do have good opportunities, whether it’s mouthwashes or otherwise, to help kind of control the symptoms related to mucositis. And it’s so essential, because you want patients to be able to maintain eating as well. And if your mouth is raw, you’re not going to want to eat. And as you don’t eat, you may not maintain that strength that you need to continue with treatment and kind of get through treatment safely.

Katherine Banwell: 

Yeah. Yeah, that’s good advice. Care partners play an important role in helping patients during their treatment. How can they support patients in advocating for the best possible care?

Dr. Anand Patel: 

I always try to communicate to my patients that, when possible and when able, going through the journey of AML alone is incredibly daunting and very difficult. So, leveraging that support system around you, whether it’s friends, families, other sorts of advocates that may be in your life, that is key and essential. And the reason for that is, when patients are feeling at their worst, is when it’s the hardest to do those sorts of things like communicate, or pick up the phone call, or push for something specific to be done.

Having a care partner, someone who is there with you that knows what your preferences are, that knows, through years of interaction with you – again, whether it be a spouse, a family member, a close friend, whoever it may be. Having that person, and really empowering them to say, “If I’m not feeling well, if I’m not feeling like myself, I know that you will be able to speak up for me and be able to communicate what is important to me.” I think that is incredibly valuable.

With that, the earlier those discussions happen with a patient and the support system around them, the better it is. Because when you are at your sickest, again, is when it’s hardest to make sure that the people around you know exactly what it is that is important to you, versus not. So, oftentimes, I encourage patients to have these conversations, even when the diagnosis is first made. That, “Who do you see as your support system around you?”

“Who are the people in your life that you see as your best advocates? And have you had the opportunity, either before this diagnosis or since, to communicate with them what all it is that’s most important to you? And when you want them to kind of step up for you and be your primary communicator if needed or make sure to voice concerns that you have, if you aren’t comfortable voicing them.”

Katherine Banwell: 

As we close the program, Dr. Patel, I wanted to know what gives you hope about the future of AML testing and treatment.

Dr. Anand Patel: 

Yeah, I mean, I am incredibly hopeful about where we are going with AML. And a lot of that is based on where we’ve kind of been in the last decade. So, a little earlier in this program, I mentioned that for over 50 years, we kind of had one tried and true regimen for AML. Since 2017, the number of approvals for AML, in terms of standard new, approved drugs that have shown to be beneficial, I think it’s up in the double digits now.

I joke that I have a slide that I need to keep updating about the new therapies that we have available. So, that’s a good problem to have. It’s one that I hope to continue to have. And with that, as you have more effective drugs, I think you can then offer the chance of remission, the hope of cure, to more patients. Also, there’s a route to remission that may not be as intensive from a side effect profile for patients, depending on how you can combine these therapies, or otherwise.

So, the fact that we have this roadmap ahead of us that’s becoming increasingly more nuanced and complex is actually a good thing. In general, if you have one option to pick from, and historically, that option has not been one that cures virtually every one of their disease, it means you need a more complex and nuanced roadmap, and that’s kind of where we’re at in AML right now.

Katherine Banwell: 

Well, that is a very promising outlook to leave our audience with, Dr. Patel. Thank you for joining us today.

Dr. Anand Patel: 

Thanks so much for having me. It’s truly been my pleasure.

Katherine Banwell: 

To learn more about AML, and to access tools to help you become a proactive patient, visit PowerfulPatients.org. I’m Katherine Banwell. Thanks for joining us.