Treatment Approaches in AML: Key Testing for Personalized Care

Treatment Approaches in AML: Key Testing for Personalized Care from Patient Empowerment Network on Vimeo.

When it comes to Acute Myeloid Leukemia (AML), genetic testing (or biomarker testing) is essential in helping to determine the best treatment approach for YOU. In this program, AML expert, Dr. Naval Daver reviews key decision-making factors, current AML treatments and emerging research for patients with AML.

Dr. Naval Daver is an Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. More about Dr. Daver here.

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Transcript:

Katherine:                   

Welcome to INSIST! AML. A program focused on empowering patients to insist on better care. Today we’ll discuss the latest advances in AML, including the role of genetic testing and how this may affect treatment options. I’m Katherine Banwell, your host for today’s program. And joining me is Dr. Naval Daver. Welcome, Dr. Daver. Thank you so much for being here. Would you introduce yourself?

Dr. Daver:                    

Hello. Yeah. Thank you very much, Katherine. It’s a pleasure to join this discussion and meeting. I’m the Associate Professor in the Department of Leukemia at the MD Anderson Cancer Center. I focus on the treatment of acute myeloid leukemia and MDS, including the development of a number of clinical trials that are using targeted therapies and immune therapies for this disease. And with the great and dramatic progress, we’re seeing in acute myeloid leukemia; I think it is now more important than ever for patients to be aware of the options and be able to select the most appropriate therapy with their physicians.

Katherine:                   

Before we get into the discussion about AML, a reminder that this program is not a substitute for seeking medical advice. Please refer to your own healthcare team. Dr. Daver, I know the field of AML research is advancing rapidly. Would you give us an overview of the current treatment types in AML?

Dr. Daver:                    

There has been dramatic progress in the treatment of acute myeloid leukemia, especially in the last three years. We’ve had eight new drugs approved for the treatment of acute myeloid leukemia. The most progress I think that has happened so far is in the identification of particular molecular mutations and targeting those mutations with targeted therapies.

The mutations that are most important right now and have target options for FLT3 mutations, F-L-T-3, and the drugs that have been USDA-approved for this are an agent called Midostaurin, which is a first-generation FLT3 inhibitor and combination chemotherapy.

And then, more recently, another agent called Gilteritinib, as a single agent in relapse refractory FLT3 AML. The other mutational group that is also very important, and therapeutically needs to be checked, is IDHN1 and IDH2. And there are now two IDH inhibitors, IDH1 inhibitor, Ivosidenib, and IDH2 inhibitor, Enasidenib, both of which have been approved by the United States FDA for relapse patients with IDH1, IDH2 mutations. So, I think it’s really critical now to check for particular molecular mutations and to appropriately add the particular targeted therapy or select the particular targeted therapy in patients who have the mutation.

The other major area of advancement, and probably, if not the most important breakthrough that has happened, is the development of a new drug called Venetoclax. This is a BCL2 inhibitor. It’s new in AML, but in fact, it has been used for many years in CLL, which is chronic lymphocytic leukemia.

And this drug, in combination with Azacitidine in the frontline setting in older patients with AML who are not good candidates for intensive induction, has shown very high response rates, almost 70 percent CR-CRi, which is more than double of the 20 to 25 percent we were getting with Azacitidine alone.

And it’s now been approved by the US FDA and, in my opinion, and many of the experts really is the new standard of care and should be used in all older patients who are not good candidates for intensive chemotherapy given both the very high response rates, as well as now mature data showing significantly improved overall survival and a good tolerability.

So, there are many other breakthroughs. But I think these targeted agents, and Venetoclax, probably are the most impactful today.

And we’re focusing a number of new combinations building around this.  

Katherine:                   

What are common mutations in AML?

Dr. Daver:                    

Yeah. So, the most common mutation in AML is F-L-T-3, FLT3 mutation. This is both prognostically important mutation, presence of an FLT3 in a newly diagnosed AML, has been shown in many large publications by the German Cooperative Group, British Cooperative Group, our group, and others, is associated with an inferior survival.

Also, now, on top of that, it is also a therapeutically important mutation in addition to having negative prognostic value because the addition of FLT3 inhibitors seems to dilute, to a large extent, the negative prognostic value.

So, we believe that if we can identify FLT3 mutations at FLT3 inhibitors, we can definitely improve the outcome of those patients. The second most common is what we call NPM1 mutation, and that tends to occur with FLT3. About 55 percent of patients with an FLT3 mutation will have a coopering NPM1.

NPM1 is very interesting. With NPM1 mutation is present on it’s own without a FLT3, it’s actually associated with favorable outcome. It’s a favorable prognostic marker. However, if NPM1 is present with a FLT3, and especially if the FLT3 has a high quantity, high allelic load, then the NPM1 loses its favorable impact. So, now we’re kind of moving beyond just; do you have one mutation or not, which is what we thought 10 years ago, to; well, yes, you have this mutation, but what about the core-occurring mutation and even beyond. What about the burden, or what we call the variant allele frequency of that mutation?

So, for good or bad and I think it’s good in the end because it’s going to improve the patient outcomes, that we are getting more, more in-depth and there’s no longer quote, unquote, AML.

So, there’s a lot more granularity and analysis that is required even before starting treatment. And this is the thing that, in the community, we’re educating the doctors a lot, is that it’s okay to wait four to six days, especially if the patient does not have a very proliferative leukemia, to get the important bloodwork to identify the appropriate molecular and chromosome group.

So, that we can select the right treatment which will improve outcome rather than just rushing into standard treatment and missing a particular molecular chromosome group.

Katherine:                   

True. It might not be – the genetic testing might not be right for everyone.

Dr. Daver:                    

Right. Right.

Katherine:                   

What is genetic testing in AML?

Dr. Daver:                    

So, genetic testing in AML is basically what we call molecular profiling.

So, it’s looking at the presence of particular molecular mutations. For example, at MD Anderson, we do what we call 81 gene panel. So, this looks at 81 different genes for mutations in the bone marrow of newly diagnosed acute myeloid leukemia. Now, how did we come up with 81 genes? So, this was actually done by literature analysis and review of previously published preclinical and translational studies, and we basically selected all mutations that had been shown to occur in two percent or more of thousands of AML patients. And we found 81 such mutations. So, that any mutation that had a two percent or higher frequency in known published or public databases was included.

And that’s how we’re able to analyze for the mutation. So, it’s still possible that there may be some very rare mutations that are present, and those may be important for research. But they don’t change our treatment decision today. And so that’s what we call genetic profiling. Some people call it molecular mutation analysis. Some people call it next-generation sequencing.

But basically, this is looking for mutations in particular genes that are known to occur in AML. Now of those 81 genes; and some people do a 100 gene panel, some do 50, so those are variables; but among those, there are four or five that are most important: the FLT3, as we discussed, where we can use FLT3 inhibitors; IDH1 and two, because we can use IDH1 and IDH2 inhibitors; TP53 is a very important mutation because it has very high risk and adverse prognosis.

And there are now new drugs coming that may be very effective in TP53. So, we are checking for that. Those drugs are in trials, but the trials are showing very promising data and could be a great option if a patient is known to have a TP53.

Those drugs are Magrolimab, CD47 antibody, and APR-246. So, these are the four most important therapeutic mutations.

There are also some mutations that have prognostic value even though we cannot target them. These include mutations like RUNX1, DNMP3A, ASXL1.

One does not need to know the list. But the point is that these mutations may help determine whether a patient falls into intermediate-risk group or high-risk group, which then impacts the decision as to whether we need a stem cell transplant or not. So, it really is important to get this molecular profiling. It’s actually available in the United States commercially. And any clinic or hospital is able to actually order it. And insurance will cover it in 100 percent of the cases.

Katherine:                   

Wow, that’s great. What should – when should patients be tested, and how is testing done?

Dr. Daver:                   

Yeah. So, the basic testing for any suspected new acute leukemia is to get a bone marrow biopsy. That has to be done.

That should be done very quickly because all of the information that will be generated to make the treatment decision will come off the bone marrow biopsy.

Katherine:

What about retesting, Dr. Daver? Is that necessary?

Dr. Daver:                    

Yeah. So, retesting is necessary in – not for everything, I think.

But let’s say someone had treatment induction and relapsed a year later. So, we would definitely retest: 1) to confirm with the bone marrow’s relapsed AML, get the blast percentage because we need that before restarting treatment, so we know what was the starting point to know how the patients doing after treatment if he’s responding. 2) Molecular testing, for sure, should be repeated. We usually repeat the molecular testing such as FLT3, IDH1, IDH2, because there are drugs that can target these mutations in a relapse.

And more interestingly, we actually have published, and other groups have also published, that there are some patients who may not have those mutations at baseline but may actually acquire or have detectible mutations at relapse. So, if you don’t have FLT3 at baseline, your physician may assume that the FLT3 is not there, not do mutational testing. But in fact, that may not be true. So, it is important to retest about 15 percent, one five percent, in our publications can acquire a detectible FLT3. Which is critical because this could then change your treatment.

IDH1 and two are rarely lost or acquired, but we have seen a few five percent or so cases of that. So, it’s still better to check for that. And then TP53 we check for because now we have these new research clinical trials, phase one, two, that are showing some very encouraging activity in TP53. So, these are probably the main things to retest for.

There’s also some new clinical data emerging with a new drug called menin inhibitor that targets a particular chromosome abnormality, MLL rearrangement. This is again in a phase one setting, so the data may not be widely disseminated. But we’re seeing some very encouraging activity with menin inhibitors.  

And so, we are 100 percent checking for the MLL rearrangement chromosome, which can be done on FISH, or routine chromosome.

And if that is there then trying to get on one of the menin inhibitor trials, they’re opening about 25, 30 centers with different menin inhibitors, would be a very, very good option because we think these will be the next molecular or chromosome-targeted breakthrough in AML.

Katherine:                   

We’ve been discussing how molecular testing results lead to targeted therapy. How do targeted therapies work?

Dr. Daver:   

Targeted therapy means that we’re targeting a particular mutation. Now we may be targeting in different ways. So, some of the drugs, like FLT3 inhibitors, these are the most established and oldest targeted therapies in acute myeloid leukemia, been in development for about 18 to 20 years, work by blocking a particular receptor, the FLT3 receptor.

That receptor, when blocked, removes the growth and proliferation signal to the leukemia blast. And that receptor is much more preferentially and heavily expressed on the surface of the acute myeloid leukemia cell as compared to the normal, healthy myeloid or lymphoid cell. So, basically, we are shutting down the growth signals, resulting in eventual death of the leukemia blast and that’s how FLT3 inhibitors work. So, it’s a more of a direct activity resulting in cell death over a few days and quick action. On the other hand, we have what also is called targeted therapies but act very differently. These are IDH1, IDH2 inhibitors.

So, when you use an IDH1 or two inhibitor, they do go to the IDH1 and two receptor on the surface of the acute myeloid leukemia cell, but actually, they don’t result in the death of the cell. They actually cause what we call differentiation.

So, they promote that immature abnormal leukemia cell to undergo maturation and become a normal myeloid cell, which, over time, will die because normal cells have a finite lifespan, and they will die. As compared to leukemia blasts, which can live on much, much, much longer. And so, this process is called differentiation. So, FLT3 inhibitor, very different direct cell death. IDH inhibitor, very different from most maturation differentiation of immature cells to mature cells and takes longer. So, this is important clinically because with FLT3 inhibitors. We see responses quickly, one to two months. IDH inhibitors it takes longer, three to five months.

And so, targeted therapy is not one and all the same. You may be targeting a particular receptor, but the modality of action downstream may be very different.

Katherine:                   

What’s the treatment regimen for targeted therapies, and how long are patients treated with these types of therapies?

Dr. Daver:   

Yeah. I mean, that’s an area of big research. There’s no one field of answer yet for – and I don’t think there will be.

Of course, eventually. So, it really depends on; 1) What setting we’re using it in? Newly diagnosed, relapsed AML. In relapsed AML, with most targeted therapies, whether you’re use is a single agent, like FLT3, IDH1, IDH2, TP53, MLL-targeted agents, the goal is to get a patient to transplant.

Transplant, meaning allogeneic stem cell transplant using a sibling donor or a match-generated donor.

Because in relapsed AML without transplant, irrespective of the genetics and chromosomes, all relapsed AML have very poor outcome. The survival is only 20 percent or less without transplant.

If we can get a patient to transplant, we do have a good chance of long-term survival. So, the goal is transplant. And we usually use a targeted therapy for short, finite period, two to four months, to get a remission, get to transplant, hope that will cure the disease.

In front line, it’s quite different. We’re using induction chemotherapy with FLT3 inhibitors. In some research trials, we’re adding IDH1 and two inhibitors. We’re using Venetoclax, which is a kind of a targeted therapy.

Also, the BCL2 in combination with hypomethylating agents. And here, the targeted therapy is often used indefinitely. At least for one or two years. But in our approach and our guidelines, we continue the FLT3 inhibitor, IDH1 or two inhibitor or Venetoclax, as long as patient is tolerating it and does not have disease progression.

So, these are being used kind of similar to CML, chronic myeloid leukemia, where we use tyrosine kinase inhibitors or myelofibrosis, where you use jak inhibitors. They don’t cure the disease, but they continue to control the disease as long as you take them.

And in the end, we call this functional cure.

If somebody takes a FLT3 inhibitor and lives 20-plus years, semantically, he was never a cure, like an infection gets cured. But functionally, to me, he lived a normal life, and he was cured.

Dr. Daver:                    

And so, that’s how we’re using those inhibitors in the frontline setting different from the relapse setting.

Katherine:                   

How do these newer therapies differ from more traditional chemotherapy?

Dr. Daver:   

Yeah. Dramatically different. Completely different from traditional chemotherapy. So, to put it in more layman terms, traditional chemotherapy is like a nuclear bomb. Right? You – There’s a lot of things there in the marrow. You don’t know what’s good. You don’t know what’s bad. Blow it all up and hope that, when the new plants grow, the good ones grow and the bad ones were kill. And, in fact, this is true, to a large extent. Traditional chemotherapy, not to put it down, is actually been curative in a large population of AML for the last three decades. Our group and British MRC and Polish, and many groups have published up to 50 to 65 percent cure rates, especially in younger patients, below 65, with traditional chemotherapy.

So, this is not bad. People always get depressed with leukemia. But if you look at solid tumors, I mean, they have never achieved cure rates above 10 to 15 percent till the last decade or so. So, we were still getting 60, 65 percent cure rate. Two out of three.

So, traditional chemotherapy has done great work. But it was that approach. Just nuclear explosion. Take it all out, and hope good stuff comes.

Now the targeted therapy’s like a sniper. It’s actually looking for the particular leukemia cells and trying to take them out one by one with minimum collateral damage to your healthy bone marrow cells, which are important to produce red cells, platelets, white cells. So, guess what? There’s much less toxicity. You don’t see the hair loss with these agents. You don’t see the mouth sores and mucositis. GI complications are much less; infection risk is usually less.

Not to say they don’t have their own side effects. Unfortunately, even the targeted therapies have unique side effects. But, in general, those side effects are much less impactful in a negative quality-of-life way and much more manageable and tolerable. So – And, in the end of the day, they’re actually often more effective.

So, for example, with the FLT3 inhibitor, the study that was done with Gilterinib and Quizartinib, two very potent FLT3 inhibitors, was looking at a single-agent FLT3 inhibitor versus three-drug, high-intensity combination nuclear chemotherapy. And if I told this to any layperson, they would say, oh my God, that’s completely unfair comparison. You’re going to use three drugs, IV chemo, strong chemo, and compare it to one oral targeted pill. There’s no way the pill can be even equal, leave apart, win.

But guess what? The targeted therapy actually won. It not only was equal. It doubled the response rates, it reduced the toxicities and early mortality and led to improved overall survival, the gold standard. So, this shows that even though they are sniper, they can actually be much more effective with less toxicity. So, it’s a win-win. Better, tolerable, and more effective. Now the next stage within then decade, we think, it’s not one or the either, it’s really a combination. So, we’re reducing the dose of chemotherapy. So, we’re not making it as nuclear as it was. It’s still intense. But much more tolerable. And we’re compensating for that by adding the targeted therapy.

And, in fact, in the end, we expect much higher responses and survival with much better tolerability and lower early mortality. But I don’t think we’re at a stage where traditional chemotherapy is gone. Maybe 10, 12 years from now, as many more developments come, we’ll get there. But I think it still has a role, especially in the younger AML patients.

Katherine:                   

Dr. Daver, you mentioned the – some common side effects of chemotherapy. What about some of the newer therapies? Do they also have side effects?

Dr. Daver:                    

Yeah. Absolutely. I mean, every therapy we have in leukemia has a side effect. There’s no drug I can mention that is just devoid of them. Of course, some are less, and some are more. So, to be more specific, I think, for example, IDH1, IDH2 inhibitors, these are probably one of the most tolerable treatments we have in all of leukemia treatment. In general, they don’t cause much myelosuppression. Meaning, drop in blood counts. They don’t cause hair loss. They don’t cause mouth sores and GI upset in majority of people.

They’re always some patients who may. But what they can cause are two things: Number one, is they can cause what we call the differentiation syndrome.

And differentiation syndrome means the blasts that are going from the immature state to the mature state; in that process, they can cause an inflammatory reaction. And this can manifest with fever and cough, and chest pain, hypoxia. It’s something that’s actually very, very easily treatable, giving steroids for three or four days will take care of it. But many times, people were not aware of this. And so, often, we saw this was missed in the community.

So, that’s one specific example. With the FLT3 inhibitors, sometimes we see that they can cause more prolonged drop in blood counts, and count recovery can be delayed. Or we can sometimes see that they may cause some cardiac signals; increase in cardiac intervals. Again, something that, with close monitoring, bloodwork, keeping the electrolytes normal, can be managed. But I don’t want to go through the whole list. But the point is that there are specific and unique side effects that can be seen with particular targeted therapies.

And again, this is a learning curve where we have done these trials for eight to 10 years. So, we became familiar. But when the drug is approved, it’s a – it’s kind of a night-and-day situation in the community. They didn’t have the drug yesterday. They have it today. But there may not be any learning curve there. So, I think that’s where a lot of education and interaction with our colleagues is now coming into play.

But also, patients, I think, need to take this a little bit into their own hands, and also read about the label, read about the drug. So that, if they have side effects, if they actually ask their doctor and say, do you think this could be differentiation? I read about it. Yeah, most people will at least think about it. And I think this could be helpful to make sure that things are not missed. So, we do want patients to be more interactive and kind of  take things into their own hand. Because there are so many new drugs out there that their doctors may not be fully familiar yet.

Katherine:                   

Well, let’s talk about patient advocacy. What are some of the key tests that patients should ask for after they’ve been diagnosed?

Dr. Daver:                    

Yeah. Absolutely. So, I think the key things that patients should want to get the information is: 1) Knowing the bone marrow blasts.

I mean, that’s really basic. Just knowing what leukemia it is. What are the blast percentage? 2) Is, I think, chromosome analysis is very critical to get that information and to make sure we’re not missing acute promyelocytic leukemia, or core-binding factor leukemia, which have different treatments and very favorable outcomes, and would never, in general, never require a allogenic transplant. At least in majority of cases.

And 3), which is the one where we still see that it may sometimes not be available or be missed, is molecular testing.

I think it’s very critical to request molecular testing. And among molecular testing, especially FLT3, maybe IDH1 and IDH2, and TP53.

So, I think these are the most important data sets. Cytogenetics, key molecular mutations, bone marrow blasts, and confirmation of the type of leukemia before we embark on any treatment.

Katherine:                   

How can patients feel confident, do you think, in speaking up, and becoming a partner in their care?

Dr. Daver:   

Yeah. I mean, this is always a touchy area because physicians may feel that this is kind of encroaching on their territory or telling them what to do. And this is always a major challenge. I think when you go for the clinic visits, just to have a list of your questions written down and having them prepared and prioritizing them.

I always say, have your top-three questions ready.

We’ll try to do the others. But we’ll do the top three. And I think, when you have a new diagnosis of AML, the top three should be: what is the type of leukemia I have, and what are the bone marrow blasts? Number one. Do we have any chromosome and molecular information? Number two. And number three: Are there any specific treatments for my specific AML based on that chromosome molecular information? Or do we need additional information, and can we wait for that safely? I think these are the three very reasonable questions which, I think again, most leukemia experts will automatically be discussing this.

But, I think, for a patient, I think that’s important information to make sure they get before proceeding. If there’s time, the fourth question will be: Is – Are – Do we have a choice between high intensity, low intensity? And if we do, what are the pros and cons? In some cases, there may be a choice. In some cases, it may very clear that high intensity is the way to go, or low intensity is the way to go. But still, I think it’s often good to discuss that with your physician.

So, these are probably the four things one can bring up reasonably without the physician feeling that this is going to take forever, and I cannot discuss this. And then a lot of the AML treatment happens in-patient. So, there will be a lot of time for additional discussion. I tell my patients that, look, once we get the basics and the treatment decided, which is what we do in clinic, then you’ll be in the hospital most of the time. If it’s induction chemo for four weeks. Even if it’s Venetoclax, often they’re admitted for five to seven days, they will have more time then to discuss with the physician, the nurses, on a daily basis, and get more of the nitty-gritty.

Things like diet, exercise, lifestyle. Can I meet friends? I think you should not try to bring those things up right in the first visit. Because that may dilute the key information. So, I think staggering it, keeping in mind that many physicians are extremely busy, and getting that information in pieces over time, is probably productive for you and for the doctor.

Katherine:                   

With Covid-19 affecting all our lives right now, what should AML patients be considering at this time?

Dr. Daver:   

There’s a lot of guidelines on general approaches to managing things in COVID. And all of those guidelines heavily center, as we would think intuitively, on precautions.

Hand washing, minimizing contact, avoiding crowded places, trying to get treatment, potentially locally, if there are equivalent options available. We have not changed any of our frontline – we discuss this a lot every week in our faculty meeting.

This is discussed especially, as you know, because Houston currently is a major center affected heavily by COVID, and so, we have discussed whether we should move in a universal way to lower-intensity therapy for all patients. And we haven’t. And there’s pros and cons to that. When we do induction chemotherapy higher intensity, we, in fact, admit our patients for 28 days.

o, actually, even though it’s high intensity, the patient is more protected because they are in the room. Isolation rooms, sometimes. And they have minimum contact with outsiders. So, with COVID, actually, there’s very little opportunities or chances for them to get it. But the chemo is intensive. So, if they did get COVID, then it could be much more difficult or risky, or even fatal. On the other hand, low-intensity therapy is good because it’s low intensity and the risk of COVID, the frequency may or may not be changed; we don’t know. But the intensity we think could be lower because the immune system has not been suppressed.

However, low-intensity therapy very often is given outpatient. And so, then you have the benefit of lower intensity but the risk that you are going to be driving back and forth to the medical center, getting bloodwork, exposed to people in the waiting room, this and that. So, what we decided, after a lot of discussion among a big leukemia expert faculty in our group, was that we will still decide the optimum treatment based on the leukemia chromosome, molecular, age, fitness of the patient like we’ve always done.

And then we just have to try to encourage the patients to do as much precautions as possible. The other thing with the COVID, I think is very important is that, even though you may not be able to travel to your academic institution nearby because it’s harder to travel now, it’s still a good idea to try to get a consultation. We are doing a number of phone or email consultation, either directly with the patient, and even more frequently with their community doctor.

So, I get every day, four or five emails from academic even, and community physicians just saying, I have this patient, new AML, relapsed AML, whatever the case may be, here’s the mutation chromosome information, and I was going to do this. But the patient asked that I run this by one of my top academic colleagues. So, maybe MD Anderson. Some, I’m sure, are talking to Sloan. Some are, I know, are talking to Dana Farber. Cornell, whatever it may be. So, you can always request that. And maybe 100 percent of physicians may or may not do that.

And we’re seeing this collaboration actually. One of the positive things of COVID is we’re seeing these collaborations becoming better and better over time.

Katherine:                   

Oh, excellent. If a patient does need to go to clinic for a visit, what safety measures are in place?

Dr. Daver:   

Yeah. So, there’s a few things we’re doing in clinic is; one is we have staggered our clinics. So, instead of having everybody come at 9:00 or 10:00 a.m., and having 30 people in the waiting room, we really have more time slots.

And we ask people to come three of them at a time in the waiting room. We’re minimizing it three to five patients at most

Of course, there’s a lot of sanitization, dispensation units everywhere, encouraged to use those. The other important thing which, unfortunately, is a double-edged sword, is that we have had to minimize the number of friends, relatives, spouses, that can come with patients.

In fact, the policy at MD Anderson, like most cancer centers, is that nobody is allowed with the patient unless the patient is physically really impaired, as in wheelchair-bound or cannot go to the restroom. Of course, there are exceptions. But generally, I know, and I actually benefit a lot from it too, when patients have their family because the emotional support also helps our medical team to get information across. The patient may be sometimes stressed and forget things. So, what we’re doing more and more is doing phone calls.

So, what I would recommend is, as soon as doctor comes in, say, hey, doctor, can I call my daughter or my wife? I want her to listen to everything. Perfect. I don’t mind. There’s a speaker on. Good.

So, that helps with communication. But those are the big changes we have done from the clinic perspective. Still seems to be working relatively smoothly. We’re still seeing almost about the same number of patients in clinic that we were before COVID. And we have, fortunately, and knock on wood, not seen big numbers of leukemia patients with COVID. And we think the primary reason is because leukemia patients are just very cautious from the beginning. Even before COVID, they knew the risks, and we want them to continue that as much as possible.  

Katherine:

Dr. Daver, thank you so much for joining us today.

Dr. Daver:   

Thank you very much. Always a pleasure.

Katherine:

And thank you to all of our partners.

To learn more about AML and to access tools to help you become a more proactive patient, visit powerfulpatients.org. I’m Katherine Banwell – Thank you, Dr. Daver.

Confused About AML Genetic Testing and Treatment? What You Need to Know

Confused About AML Genetic Testing and Treatment? What You Need to Know. from Patient Empowerment Network on Vimeo.

What is AML genetic testing? Dr. Alice Mims explains genetic testing in AML, including the necessity of testing, the effect on treatment decisions, and why patients should be retested over the course of their disease.
 
Dr. Alice Mims is a hematologist specializing in acute and chronic myeloid conditions. She serves as the Acute Leukemia Clinical Research Director at The Ohio State University Comprehensive Cancer Center – James.

See More From INSIST! AML

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How is Acute Myeloid Leukemia (AML) Treated?

 

Effective AML Combination Treatment: Pairing Old and New Therapies

 

AML Genetic Testing Explained

Transcript:

Dr. Mims:

So, in regards to older treatments and being effective, seven plus three, which is an intensive chemotherapy, is still the standard of care treatment for patients with favorable risk AML, if they’re candidates for intensive treatments because it is potentially curative. And 7 + 3 is also the backbone for newly diagnosis for patients with FLT3 mutations, we add a FLT3 inhibitor called Midostaurin onto that, as it’s shows to improve overall survival with the addition of that compared to just the chemotherapy alone.  

And also, hypomethylating agents, which are a less intensive treatment, were the standard of care for patients who couldn’t tolerate intensive chemotherapy.  

And now we’re seeing the addition of other agents being added to this, like the BCL2 inhibitor of Venetoclax 

And recent data in phase 3 trial comparing the hypomethylating agent alone versus adding that agent did show an overall survival advantage. And so, these are definitely evolving, and I think as we are learning more about targeted therapies and how they can best be used in combination with chemotherapy other than single. Agent. But you give two targeted therapies together and having even better outcomes. We hope we continue to make improvements from where we were even just five years ago and do a better job for. 

What Is the Impact of Cytogenetics on AML Care?

 

What Is the Impact of Cytogenetics on AML Care? from Patient Empowerment Network on Vimeo.

 Understanding the cytogenetics of your acute myeloid leukemia (AML) can help determine which treatment option might be best for you. Registered nurse Mayra Lee defines this complex term and the role it plays in AML care.

Mayra Lee, RN, is an outpatient clinic nurse at Moffitt Cancer Center. Learn more about Mayra Lee.

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Transcript:

Cytogenetics would be the term that I would say patients are unaware of and don’t understand it quite often. It’s probably the first time you hear it when you come and sit down and we talk about the disease because the first thing you want to know is what is my prognosis and what is the treatment. Well, a lot of that is made through the cytogenetics of the disease.

We use these terms and we don’t often explain what all of that means. And what that means is that the disease itself has chromosomes, has mutations, has genetic information that will help us determine which treatment is a better option for you or is there a genetic mutation that you perhaps have that we now have medications that are used to treat that genetic mutation as a said just a few seconds ago. Like for the three, if you have that mutation, we now have medication to treat that where we didn’t have that five years ago or even four years ago.

 So, that terminology of cytogenetic and biomarkers are very new. They’re not something that the general public knows or understands very well.

But when you come to academic centers like where I’m at right now that is all we’re going to talk to you about because we want to do personalized medicine. And personalized medicine means what is it that your disease looks like because your disease does not look like the other AML patients. Your disease is your disease and it looks different and it’s going to behave differently. And so, we want to know about those mutations. So, so much of your treatment, so much of the prognosis is so closely linked to that that I think it’s an important thing to know. It’s important to understand it. It’s important to ask. It’s important to pause your doctor and your nurses and say, “I don’t understand what you mean by that. What does that word mean? Can you explain that to me?”

AML Genetic Testing: Could It Lead to a Targeted Treatment for You?

AML Genetic Testing: Could It Lead to a Targeted Treatment for You? from Patient Empowerment Network on Vimeo

AML expert, Dr. Pinkal Desai, outlines the reasoning behind the necessity of cytogenetics and molecular testing when managing an AML diagnosis. Want to Learn More? Download Your AML Navigator Resource Guide, here.

Dr. Pinkal Desai is an Assistant Professor of Medicine at Weill Cornell Medical College and Assistant Attending Physician at the New York-Presbyterian Hospital. More about this expert here.

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Transcript:

Dr. Pinkal Desai:         

So for patients who are undergoing molecular testing or any diagnosis of AML, both cytogenetics and molecular profiling are important, so they do not supersede each other. This is the conglomerate information that we need from the diagnosis to make important medical decisions. Usually the diagnosis would include: looking at the cells under the microscope by the pathologist; flow cytometry, which is a way to identify the subtype of leukemia; chromosomes or karyotypic analysis, which is to look at the individual chromosomes and whether they are abnormal in these leukemia cells; and the last one would be the molecular mutations, which would be single-gene profiling of the leukemia cells.

All of these are important, and it’s not that one can be omitted. They’re all part and parcel of the diagnosis of AML, and all of them should be done.  

So my advice to patients whenever this topic comes up of molecular mutations is always an unequivocal – there should be no question that this should not be done. The advice is plain and simple. This has to be done at diagnosis and, in certain cases, at relapse as well in order to figure out the best treatment possible. If they’re at a site or a clinic where this molecular testing is not available, then they should seek a second opinion to a site that would do this testing because in this day and age of leukemia, there is no treatment and diagnosis that can be done without all of these components in place.

In the old days, we didn’t have a lot of treatment in AML. It was either chemotherapy or hypomethylating agents, and that’s it. But now we have several drugs, five or six of them, that were just approved in the past two years specifically for leukemia and targeting some of these mutations. We have Midostaurin, Gilteritinib, Ivosidenib, Enasidenib, and I don’t want to go on and on about these drugs, but the most important thing is that in this day and age where you have so many drugs, how to incorporate these drugs into the management for patients, both upfront and in the relapse setting, it’s extremely relevant to do this testing, and this is highly encouraged and should be done as part of the diagnosis and treatment.

What’s Next in AML Treatment and Research?

What’s Next in AML Treatment and Research? from Patient Empowerment Network on Vimeo.

Dr. Pinkal Desai, an AML specialist, discusses research in-progress on MRD testing and pre-disease mutations in leukemia.

Dr. Pinkal Desai is an Assistant Professor of Medicine at Weill Cornell Medical College and Assistant Attending Physician at the New York-Presbyterian Hospital. More about this expert here.

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Transcript:

Dr. Pinkal Desai:         

So we at Weill Cornell are a big leukemia center, and we are leading a lot of the clinical trials in AML, both in the upfront and the relapse setting. There are several research initiatives that we are highly interested in. One of them is how to incorporate some of these targeted treatments, both in the upfront and in the relapse setting.

The most important one that we’re actively working on is to monitor these patients, so MRD testing, or minimal residual testing, is extremely relevant in order to figure out whether the treatments are working in the right fashion, and would you change treatment or would it impact the patient’s overall survival if some of these mutations persist or not.

And we are really interested in monitoring these patients and these mutations to figure out a plan which is targeted not only for the mutation but also for the specific patient, and that is one of the things that we are very interested in and doing at Cornell.

We’re also looking at pre-disease mutations. There are several mutations – this is personally my research interest as well – there are certain people who are at risk of developing leukemia; for example, people who are undergoing chemotherapy for other cancers, and the presence of some of these mutations before the diagnosis of leukemia would highly be relevant because if we’re monitoring some of these people and figuring out who can develop this leukemia and can you do something about it, so this is sort of more on the prevention aspect of leukemia or secondary leukemia, which is also something we are interested in at Cornell and ongoing research is for us.

But the most important things is obviously for patients who actually have the diagnosis of AML, the best available agents as part of clinical trials, the best way to monitor them and design treatments so that we can achieve the best possible results for the patient is what we are striving for at Cornell, and it would be extremely helpful for patients to enroll into these trials and contribute both to their own treatment outcomes and also to the AML community at large.

Genetic Testing in AML: What Are Doctors Looking For?

Genetic Testing in AML: What Are Doctors Looking For? from Patient Empowerment Network on Vimeo.

Dr. Pinkal Desai, from Weill Cornell Medicine, discusses the genetic testing required in AML, including mutations and changes in chromosomes that are being identified, and how these results can impact risk and prognosis.

Dr. Pinkal Desai is an Assistant Professor of Medicine at Weill Cornell Medical College and Assistant Attending Physician at the New York-Presbyterian Hospital. More about this expert here.

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Transcript:

Dr. Pinkal Desai:         

So there are several genes that we look for, but the most important ones from a standpoint of choosing treatments and monitoring, the first one would be FLT3. There are two kinds of FLT3 mutations, ITD and TKD; both can have different drugs that target them.

This is relevant because some of the upfront management, even when we choose – in younger patients, for example, when we are choosing chemotherapy, there are approved FLT3 agents that can be added to the chemotherapy. For example, Midostaurin, that’s a FLT3 inhibitor; we use that, and it’s important to know the FLT3 results, and preferably within 48 hours from the diagnosis, in order to choose the right treatment.

The other mutations that are relevant are IDH1 and IDH2. Both of them have approved targeted treatment against them, so depending on the clinical scenario of the patient, whether it’s new diagnosis or a relapse, these mutations are important to test, and the same for FLT3 as well.

I want to clarify here that sometimes the molecular mutations are absolutely important at diagnosis, but some of these mutations are also important to be retested in people who have relapsed because it’s not always the case that what is present at baseline may be the same at the time of relapse.

It’s possible that the clone is different, so some of these targeted mutations against which we have drugs, like FLT3, IDH, we need to test these mutations at relapse to make sure that we’re not missing them, particularly if they were present at diagnosis. The other mutation that is also relevant is TP53 because there are ongoing clinical trials that are targeting against these mutations, so the relevance of mutations are not only important in approved agents, but also in the ongoing clinical trials that are targeting these mutations.

 NPM1 is the other important mutation that is important in risk profiling, as well as monitoring over time to see if we can anticipate relapse or do something about it in the future.

There’s a laundry list of other mutations, but these are – I don’t think that patients should get lost into the individual mutations at the beginning. I think the relevant point here is that all of these need to be sent, and once the panel comes back with all of these mutations, then it’s time to sit down and go through, “Okay, the patient has FLT3, NPM1, plus some other mutation. What does that mean for me?” I think that’s what the patients should be asking. “Okay, I got these three mutations. I have these four mutations. Tell me how this is going to impact my care and my chances of survival?” I think that’s the most important thing.

Everybody’s leukemia is different. It’s more than a mixed bag; it’s actually unique to patients. Someone’s profile and genetic signature is different than someone else’s.

It’s important that every mutation is actually dealt with in relation to the other because it’s not just the presence of individual mutations, but the combinations of all of these mutations that are high relevant in figuring out whether this is important in the future or not. 

Why Should AML Patients Undergo Genetic Testing?

Why Should AML Patients Undergo Genetic Testing? from Patient Empowerment Network on Vimeo.

AML expert, Dr. Pinkal Desai, explains the necessity of genetic testing when AML is diagnosed, including an overview of relevant tests and how results can affect prognosis, risk factors and treatment.

Dr. Pinkal Desai is an Assistant Professor of Medicine at Weill Cornell Medical College and Assistant Attending Physician at the New York-Presbyterian Hospital. More about this expert here.

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Transcript:

Dr. Pinkal Desai:         

So the reason that genetic testing is important and the patient should go through genetic testing after a diagnosis of AML, there are several reasons, actually, and we’ll go one by one. But before I go there, I want to clarify that genetic testing in AML does not mean that we’re testing for whether the patient inherits this mutation or genetic abnormality.

This is actually a mutation or genetic damage in the leukemia cells and not in the patient’s body elsewhere, so it’s important; this is a tumor-defining test and not meant to actually figure out whether this is inherited or not because most AML is actually not inherited. The other part that I want to focus on is that this testing, genetic testing or molecular testing or molecular profiling of leukemia, as we call it, is different than cytogenetics. Sometimes patients can be a little bit confused between what is molecular profiling and what is cytogenetics. Cytogenetics are big DNA or big changes in the chromosomes, while molecular mutations are single point gene mutations, which requires a much more detailed analysis of the leukemia cells.

The reasons that this testing is important, and the other part of it is that it’s just not after; it’s actually during the whole process of diagnosis of AML. If AML is suspected, then it should be done on the diagnosis bone marrow at the time when we’re drawing the blood. Otherwise, many times patients have to repeat a bone marrow biopsy to get this testing. So if something is already suspected that we are gonna maybe find leukemia, this should be done at the time of diagnosis. The first reason, which is the most important, is that when we do this molecular testing there’s a set of genes that we test. It’s 200s, 300s; every panel is a little bit different, but generally have the best components that we care about in the AML diagnosis.

There are targeted treatments against some of these mutations, and it’s important to know these mutations before the treatment begins. Not all mutations will change the way the treatment is designed, but there are certain mutations like FLT3, IDH, where it might matter as to what you choose as the frontline or the first line treatment, so it’s important that we actually get these results, at least some of these results, by the time we decide to choose the right treatment for the patient.

The second reason this is relevant is when patients go through AML induction or the first line treatment, the goal of which is induce remission, once they are in remission, the work is not done. There are several other things that we have to do and more treatments that are designed based on this molecular testing.

For example, depending on the molecular testing and the cytogenetics or the chromosomes, we profile patients as low risk, intermediate risk, or high risk. This risk means what is the likelihood that this leukemia will come back in the future, and how would that impact the patient’s survival? Some of the post-remission treatments are designed to change depending on the results of these mutations, so it’s important to actually know this at diagnosis because then the patients would go into remission, and yet we have to make a decision on what kind of best treatment to give post-remission in order to make sure that the patient is cured, or we maximize the chance of cure in this patient.

So the kind of chemotherapy, whether to transplant or not transplant, all of this is dependent on the molecular mutations. The third reason, which is becoming more and more relevant now in AML, is some of these mutations can be monitored over time.  

 It’s a much detailed testing to know the kind of remission or the extent of remission that they patient achieves, and you can actually follow these mutations over time, even in remission, to know that – is the molecular mutation zero, is it 0.2%? This is a very upcoming field in AML, and the idea of monitoring these mutations is relevant because if you have a mutation, can you do something about it post-remission? Would that alter some of the treatments? Would that help us anticipate if a relapse is coming before the actual clinical relapse happens and the blood counts go abnormal? Can we anticipate is this patient likely to relapse, for example, six months later, and could you prevent these relapses?

These are all the reasons why these genetic testing or molecular profiling of leukemia is highly relevant in the field of leukemia. We all cannot even make a decision anymore without having this full panel. 

AML Genetic Testing Explained

AML Genetic Testing Explained from Patient Empowerment Network on Vimeo.

 Acute myeloid leukemia, or AML, has many subtypes and understanding your individual disease is key to accessing personalized therapy. Learn about the role that genetic testing plays in guiding your AML treatment options in this explanatory video. Want to Learn More? Download Your AML Navigator Resource Guide, here

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Transcript:

Acute myeloid leukemia, or AML, is a complex cancer that begins in the bone marrow.

Not all AML patients have the same disease. AML has many subtypes and understanding YOUR individual disease and subtype is key to accessing personalized therapy.

How can you learn more about your AML?

Genetic tests can provide more detail about your specific AML

These tests use laboratory approaches to identify changes in chromosomes, genes or proteins. A gene mutation is an abnormal change in a gene’s DNA sequence.

The results of genetic tests can inform your prognosis and treatment options.

The types of genetic tests that physicians use for patients with AML include:

  • Cytogenetic Analysis (or Karyotyping)
  • Fluorescence in situ Hybridization also known as a FISH test
  • Molecular Testing, which includes:
    • Polymerase chain reaction – PCR for short
    • DNA sequencing;
    • and Next-generation sequencing

Your healthcare team can help decide which test is best for you.

Genetic test results are used to identify genetic mutations that determine your specific AML subtype and help your healthcare team to better understand your prognosis, treatment path and assess how well therapy is working.

Once you have your results, there a number of targeted therapies currently available for AML.

Targeted therapies block the growth of cancer by interfering with specific molecules involved in the progression and spread of cancer. 

Targeted therapies include a class of treatment called “Inhibitors.”   AML Inhibitor therapies that target a genetic mutation include FLT3 Inhibitors and IDH Inhibitors.

Novel inhibitor therapies that are used across all mutational subtypes of AML include BCL-2 inhibitors and hedgehog inhibitors

Research is moving quickly in this field as new treatments are being studied to target genetic mutations in AML and other diseases.

How can you take action?

First, make sure you seek the opinion of an AML specialist. Discuss which tests you should undergo and review the results with your doctor. Educate yourself by doing some of your own research on the findings then collaborate with your healthcare team to determine a personalized treatment plan for your AML.  Finally, follow-up with your doctor regularly to understand when you should be re-tested.

Want to learn more? Start here.

Predictive (Familial) Genetic Testing vs. Cancer Genetic Testing: What’s the Difference?

Predictive (Familial) Genetic Testing vs. Cancer Genetic Testing: What’s the Difference? from Patient Empowerment Network on Vimeo.

Brittany DeGreef, a genetic counselor, explains the difference between hereditary genetic testing for cancer risk and genetic testing following a cancer diagnosis.

Brittany DeGreef is a Genetic Counselor at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. More about this expert.

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Transcript:

My name is Brittany DeGreef and I am a licensed and certified genetic counselor and I work primarily in oncology genetics. At the Lurie Cancer Center, what I do is I provide comprehensive genetic counseling services for patients and families. Basically, what I do is take in family and personal history.

I help interpret what patterns we’re seeing in families. I provide risk assessment. Then we order and interpret genetic testing results. Based on those results, sometimes we make medical management recommendations for patients and families within a multi-disciplinary team within oncology at Northwestern.

The difference between predictive genetic testing and cancer genetic testing – let’s start with predictive genetic testing first. This means that we are testing someone who might be at risk for a specific hereditary condition, in particular, hereditary cancer syndromes.

In this case, what we’re doing is testing someone who is asymptomatic or does not have any signs of cancer at this point. What we’re trying to do is to identify if that person might be at high risk for specific cancers and implement certain screening strategies to risk reduction procedures and implement surveillance, if needed, if someone is at high risk for specific cancers.

When we think of cancer genetic testing, this person is likely already diagnosed with cancer and what we’re doing is trying to figure out if this person inherited something from either their mom or dad that placed them at a higher risk to get cancer in the first place.

In the past, this type of testing did not impact treatment strategies. But recently, this has been kind of the forefront of medicine where we are seeing patients who are just diagnosed with cancer and they are using genetic testing information to then incorporate that into their treatment approach.

Key Genetic Testing after an AML Diagnosis

Key Genetic Testing after an AML Diagnosis from Patient Empowerment Network on Vimeo.

Dr. Elizabeth Bowhay-Carnes provides advice on key genetic tests that should take place after an AML diagnosis and how they can inform your treatment options. Download the Find Your Voice Resource Guide here.

Dr. Elizabeth Bowhay–Carnes is Director of the Adult Non-Malignant Hematology Program and Co-Director of the Adolescent/Young Adult Oncology Program at Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center.  More about this expert.

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Transcript:

Transcript: 

When a patient is first diagnosed with AML, or Acute Myeloid Leukemia, that test comes back initially as a test called flow cytometry, and that is really just one of the very first initial tests that is needed in the workup.   

AML does not have traditional staging, as solid tumors have. There’s no such thing as a stage one, two, three, four. Instead, AML is divided into different risk categories. We call those low-risk, intermediate-risk, or high-risk, or sometimes we use the term standard-risk, intermediate-risk, high-risk.  

And that information is determined from some specialty tests that we call cytogenetics. Sometimes we use the term molecular testing or next-generation sequencing. Those three different terms, cytogenetics, molecular, next generation sequencing, are all specialty lab tests that help us determine what risk category group does a patient fall in.  

So, when a patient is first diagnosed with AML, that is very important to establish the initial diagnosis, but there’s those important follow-up tests that are done over the following weeks of treatment, from diagnosis at the beginning of treatment, that determine what a patient’s risk categories are. That information is very important because when we talk about initial treatment, a lot of the time that initial treatment is the same for all patients.   

But then, there are other medications that can be added on, or different steps in the treatment process, that vary based on a patient’s individual risk category and risk characteristic. 

A Conversation With Dr. Jo-Anne Vergilio

A new year means new programs! We’d like to introduce to A Conversation With, which is a collection of conversations with healthcare leaders, including patient advocates and various healthcare professionals, to take a closer look at the topics and issues important to empowered patients, care givers, and their families.

In our first segment of A Conversation With, we spoke with Dr. Jo-Anne Vergilio the Senior Director in Pathology; Senior Associate Medical Director in Laboratory Operations, and Senior Hematopathologist at Foundation Medicine, Inc. Dr. Vergilio discusses what patients should know about biomarker testing and answers the following questions:

  1. How does biomarker testing work?
  2. How does biomarker testing help a cancer patient’s doctor with determining next steps in treatment?
  3. When in a patient’s course of treatment would they want to get biomarker testing?
  4. What is the difference between different kinds of biomarker tests?
    • Single marker vs. comprehensive
    • Tumor vs. liquid
  5. What does it mean for a biomarker test to be FDA-approved?
  6. If a doctor isn’t offering biomarker testing, what are some things that patients might say to their doctor?

AML Genetic Testing and Me

AML Genetic Testing and Me Webinar from Patient Empowerment Network on Vimeo.

Genetic testing can help physicians to better understand an individual’s AML and help guide treatment decisions. So which genetic tests should AML patients have and when? In this Patient Empowerment Network program, in partnership with The Leukemia & Lymphoma Society (LLS), an expert panel discusses essential genetic testing for AML patients. Dr. Lee Greenberger, Chief Scientific Officer at the LLS is joined by AML specialist Dr. Amit Verma and patient advocate Kuldip Ahluwalia as they explain this complex topic and share tools for patients to help ensure they get the best care.