How Have Advances in Testing Impacted AML Care?
How Have Advances in Testing Impacted AML Care? from Patient Empowerment Network on Vimeo.
Recent testing advances have dramatically improved care for AML patients. Dr. Ann-Kathrin Eisfeld discusses these improvements and why every AML patient should undergo in-depth molecular testing before making a treatment choice.
Dr. Ann-Kathrin Eisfeld is Director of the Clara D. Bloomfield Center for Leukemia Outcomes Research at The Ohio State University and a member of the Leukemia Research Program at the OSUCCC – James. Learn more about Dr. Eisfeld.
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Transcript:
Katherine Banwell:
Dr. Eisfeld, the landscape of AML has changed significantly in recent years. How have advances in testing improved patient care?
Dr. Eisfeld:
It is a different world, Katherine, honestly. I mean, I started practicing in hematology in taking care of AML patients back in Germany actually in the year 2007.
Back then, there was no other testing that was available. All we were guiding and all that we had available was morphology and cytogenetics
And very often, it was very inaccurate. And we also only had two treatment kinds available. One was intensive chemotherapy, and one was something that was just a little bit better than best supportive care. So, many patients could not receive treatment. And the increase in knowledge that we have on a molecular level in AML really did two things at once. On one, we understood we had a more finetuned understanding on which patients would respond. And the second thing is that this knowledge about the molecular landscape enabled us to have new treatments available that are sometimes in pill form that can target specific mutations in patients who carry these genetic changes.
Katherine Banwell:
Should all AML patients undergo in-depth testing like biomarker testing or cytogenetics?
Dr. Eisfeld:
Yes. Every patient should do that. It can make the difference between life and death. And it can make the difference between receiving – having a hospital stay of four weeks with intensive chemotherapy versus taking the pill at home. This is very rare that this is possible. But it is possible. And of course, you – one would not want to miss this chance if it would be possible.
Katherine:
I’d like to get your thoughts on where we stand with progress in the field of AML. What would you like to leave the audience with? Are you hopeful?
Dr. Eisfeld:
I am incredibly hopeful. I hope – when I started working in hematology, as I said at that time, it was just about when imatinib (Gleevec) came out. Which is this CML pill that really revolutionized care. And so, at that time, I would be – all patients on that bone marrow transplant service had chronic myeloid leukemia. And because they all had to undergo bone marrow transplant. Then Gleevec came, and today, there are no such patients who are see or very rarely that require such intensive care.
So, I am very hopeful that in my practice time, which hopefully –and even earlier on – that there will be a time where we find targeted therapies for almost all patients.
Essential Testing | Optimizing AML Care With Personalized Medicine
Essential Testing | Optimizing AML Care With Personalized Medicine from Patient Empowerment Network on Vimeo.
Personalized acute myeloid leukemia (AML) care is becoming increasingly common, but how does it work? Dr. Ann-Kathrin Eisfeld defines personalized medicine and reviews the testing that should take place to help create an individualized treatment approach for patients.
Dr. Ann-Kathrin Eisfeld is Director of the Clara D. Bloomfield Center for Leukemia Outcomes Research at The Ohio State University and a member of the Leukemia Research Program at the OSUCCC – James. Learn more about Dr. Eisfeld.
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Transcript:
Katherine Banwell:
How would you define personalized medicine as it relates to AML care?
Dr. Eisfeld:
I define personalized medicine in AML as have a complete testing at time of diagnosis that consists of not only the morphology of the bone marrow, but we call immunophenotyping, which is looking at the surface markers, but also full review of all the chromosomes, which is called cytogenetics. And with those metaphase testing, I’m looking really at all of them and at the hot spots, which is done by a technique called FISH.
And then most importantly, for personalized testing, it also needs to consist of testing the most common, recurrent gene mutations. Changes in the tumor DNA that we know are contributing to the disease biology and also to the response of the leukemia to different genes.
Katherine:
I imagine that personalizing therapy for a patient requires a number of tests and then thorough review of the test results. Could you provide an overview of the tests necessary to help understand a patient’s specific AML?
Dr. Eisfeld:
Yes. Absolutely. There are multiple things that go in. And let me –even before we go into the tests – point out one thing. Because as we talk about individualized care – and it is also important to keep in mind that it will be also dependent on the age and of the performance status of the patient.
Because we know that all the changes that are going to be reviewed might be more or less severe depending on really the age of the patient we are discussing. The most critical aspect for every AML patient is a bone marrow biopsy and a bone marrow aspirate on which the testing that I have been referring to are performed.
One, it gives us information about how the – after review of the hematologist, it gives us information about the specific kind of the leukemic cell.
And very importantly – and this is a very more recent development that we know about that’s important. It also tells us whether the acute leukemia is really happening as an acute leukemia or whether the patient without knowing it before might have had a precursor issue. And this is something that by now really in just about half a year we can use in addition to direct treatment.
So, it seems like an ancient thing that we think that the microscopic review is important. But that is one part of it.
The second part – and this is, again, all based on the bone marrow biopsy. The inspection of chromosomes, as I mentioned, may be called cytogenetics. This test takes longer. It sometimes takes up to two weeks to result. And similar, looking at the tumor DNAs and mutations that is done either if you’re at a large institution such as Ohio State or other cancer centers. It’s done in house. Whereas at smaller institutions, it would be done by a sent-out testing that has these recommended gene mutation testings done. And some of those result just within a couple of days.
And these are – but we can talk. And I know we are going to talk a little bit more about it later, but we now have targeted therapies available. This is a really super exciting topic we couldn’t have talked about just even five years ago. And those mutations and those DNA changes come back usually within three to five days.
So, that we are able to decide on treatment.
Katherine Banwell:
How can someone ensure they’re getting an accurate diagnosis?
Dr. Eisfeld:
That’s a very good question. I think the most important part is to go to somebody who has seen acute leukemias as a living. It is a very rare cancer as you know. And if you are seen even by a general oncologist who might be a fantastic oncologist, he might just see one or two cases per year. And thus, might not be up-to-date on the newest recommendations. So, I can just advise anybody – even if he lives further away and trusts his physician a lot – to – for the diagnosis and for treatment planning, come to a comprehensive cancer center, at least for a therapy planning. Because what is now possible is many of these treatments is that we can just give advice.
And then you can still receive treatment in some cases really back at home. But be sure the testing was done correctly. And really give you every option to take into consideration what the best treatment would be for you, what the best treatment is for the patient. Having this trip – which can be hours of a drive. And I appreciate this. Having that done once would be, I think, the best thing to do.
What Is the Purpose of AML Genetic Testing?
What Is the Purpose of AML Genetic Testing? from Patient Empowerment Network on Vimeo.
How is genetic testing for AML administered, and what is the purpose? Dr. Sanam Loghavi explains the methods of genetic testing and the function of each method.
Dr. Sanam Loghavi is a hematopathologist and molecular pathologist at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Loghavi.
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Transcript:
Katherine Banwell:
Dr. Loghavi, let’s start by defining molecular or genetic testing for AML. How is the test administered, and what is the purpose?
Dr. Sanam Loghavi:
Sure. So, genetic testing at diagnosis of acute myeloid leukemia is now considered standard of care, and it must be performed for every patient with acute myeloid leukemia.
We have different methodologies of doing genetic testing, and we can use – so the best sample to perform genetic testing on is really bone marrow. But if there are circulating leukemic cells, then we can also use peripheral blood instead of bone marrow.
And the genetic tests really three main methodologies are used. One is called routine karyotyping, where we look at and characterize the chromosomes of the cancer cells for the leukemic cells. The other one is fluorescence in situ hybridization, which is another method for visualization of chromosomes, and we can look for deletions, addition of chromosomal material or certain translocations or rearrangements.
And then next-generation sequencing allows us to look for smaller changes at the DNA level. So, these are single nucleotide variations at the DNA level or smaller insertions or deletions of genetic material.
The Importance of Molecular Testing Following an AML Relapse
The Importance of Molecular Testing Following an AML Relapse from Patient Empowerment Network on Vimeo.
Why do you need molecular testing following an AML relapse? Dr. Sanam Loghavi emphasizes the importance of this essential testing and why it’s necessary following relapse.
Dr. Sanam Loghavi is a hematopathologist and molecular pathologist at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Loghavi.
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Transcript:
Katherine Banwell:
Unfortunately, relapse can happen following a course of treatment for AML. Should patients undergo molecular testing again before choosing another round of therapy?
Dr. Sanam Loghavi:
100 percent yes, that is always a yes. So, like I said, at baseline there are certain recommendations and the standard of care is to perform genetic testing.
But I cannot emphasize this enough, that AML or any cancer, for that matter, cancers tend to be smart, so they bypass the mechanisms that we try to eliminate by our targeted therapies.
So, oftentimes the genetic landscape of disease will actually change upon relapse or what we refer to as clonal evolution, and you may hear this terminology in the literature. So, it’s very important to molecularly or genetically characterize the disease at relapse before you decide how you are going to alter the course of treatment at that point.
Katherine Banwell:
Dr. Loghavi, what are you excited about in your research right now?
Dr. Sanam Loghavi:
Sure. So, I’m a pathologist, so I do a lot of molecular testing, and I also do a lot of measurable residual disease testing, and measurable residual disease tends to be one of the most informative factors in the care of patients with acute myeloid leukemia. So, these are the things that we’re very excited about, again, identifying better molecular targets of therapy, being able to measure residual disease at a more sensitive level that allows us to make better informed decisions for the care of our patients. And also, again, identifying the mechanisms of how AML develops in order to be able to eliminate the disease.
AML Targeted Therapy: How Molecular Test Results Impact Treatment Options
AML Targeted Therapy: How Molecular Test Results Impact Treatment Options from Patient Empowerment Network on Vimeo.
How could the results of molecular testing affect your acute myeloid leukemia (AML) treatment choice? Dr. Sanam Loghavi explains how inhibitor therapy works to treat AML.
Dr. Sanam Loghavi is a hematopathologist and molecular pathologist at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Loghavi.
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Transcript:
Katherine Banwell:
Dr. Loghavi, how do molecular test results impact the care plan and treatment choices?
Dr. Sanam Loghavi:
Sure. So, again, associated with really two major factors in the care of the patient. One is the decision of how intensely to treat the patient and whether or not the patient is a candidate for a hematopoietic stem cell transplant. And then the other is the availability of targeted therapies to those patients.
So, there are now several molecular alterations that make the disease amenable to treatment with targeted therapies, including mutations in FLT3, which is a name of a gene, mutations in IDH1, IDH1 or IDH2. And again, depending on the change, the patients may receive targeted therapy.
Katherine Banwell:
Dr. Loghavi, you mentioned inhibitor therapy. What is this treatment, and how does it work?
Dr. Sanam Loghavi:
Sure. So, again, it depends on the medication and it depends on the molecular change.
But essentially what happens when you have a mutation in a gene the normal function of that gene is impaired and a lot of the times that’s why you develop leukemia is because of the impairment of that normal function. So, usually what targeted therapies do, if that mutation is causing an apparent activation of let’s say a signaling molecule, then those targeted therapies will block that signaling. Or if it’s a deregulation of an epigenetic – and epigenetic means beyond genetic, so epigenetic factor, then the goal of that targeted therapy is to maintain that normal function or restore that normal function.
How Does the Presence of Molecular Markers Affect AML Care?
How Does the Presence of Molecular Markers Affect AML Care? from Patient Empowerment Network on Vimeo.
Dr. Farhad Ravandi-Kashani reviews how the presence of gene mutations can influence acute myeloid leukemia (AML) treatment choices and discusses new molecular markers being researched for future AML care.
Dr. Farhad Ravandi-Kashani is professor of medicine and Chief of the Section of Developmental Therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, TX. Learn more about Dr. Ravandi-Kashani.
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Transcript:
Laura Beth:
How do test results impact AML care and treatment decisions?
Dr. Ravandi:
So, in the first place, the presence or absence of certain mutations can be predictable outcome. Some subsets of leukemias are, for the lack of a better term, more favorable.
I personally don’t think there is anything favorable about any leukemia, but some are easier to treat, and some are easier to cure than others. There is one specific subtype called acute promyelocytic leukemia that we actually completely treat differently. We don’t use even chemotherapy in that subset of leukemia.
It has almost 100 percent success rate. And the treatment of other subsets can also be tailored, depending on these molecular and chromosomal changes. So, the initial therapy can be actually changed. There are now, for example, targeted agents that can be added to the chemotherapy, during initial chemotherapy.
And also, once the patient is in remission, depending on favorable or unfavorable their leukemia is, they may be offered allogeneic stem cell transplant. So, yes, this information is highly important. In fact, I would say crucial for our decision-making in leukemia therapy these days.
Laura Beth:
So, what is new in AML research related to molecular markers?
Dr. Ravandi:
Well, it depends on your definition of new, but FLT3 mutations are very important because they’re now several FLT3 inhibitors, and as I mentioned, the initial therapies are different, to some extent. The IDH mutations are very important, again, because they are specific targeted agents.
TP53 mutations are important because, unfortunately, they are particularly unfavorable.
This is completely hot off the press, but there are subsets of AML called MLL rearranged leukemias that can respond to these drugs called Menin inhibitors.
There are other mutations that have been discovered, many other ones, that there are no specific treatments for at the moment, but there’s a lot of research on.
Diagnosing and Treating AML: What Testing Is Essential?
Diagnosing and Treating AML: What Testing Is Essential? from Patient Empowerment Network on Vimeo.
How do test results affect the diagnosis and care of patients with acute myeloid leukemia (AML)? Dr. Farhad Ravandi-Kashani reviews essential testing for AML patients, including molecular testing and what these test results might reveal about the disease.
Dr. Farhad Ravandi-Kashani is professor of medicine and Chief of the Section of Developmental Therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, TX. Learn more about Dr. Ravandi-Kashani.
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Transcript:
Laura Beth:
Dr. Ravandi, can you define molecular testing for AML patients?
Dr. Ravandi:
We have progressed on our understanding of cancer, in general. And we have progressed in our technology, so we know that various cancers are likely caused by a number of molecular events, and this is best characterized in leukemias because we have been doing this in leukemia for many years now, simply because leukemias are much more accessible than other cancers. Leukemic cells are in blood and easily obtained and even in bone marrow, are much easier obtained than other solid tumor cancers.
And so, we’ve been able to identify a number of gene and chromosome changes that we have discovered to be prognostic, but also, have become the targets for developing effective drugs.
Laura Beth:
Beyond molecular testing, what other testing should take place following an AML diagnosis?
Dr. Ravandi:
I mean, the classical patient presents because there is something in their blood counts, so they usually have had a blood count testing done. And, of course, you need to do a number of other tests, for example, the chemistry profile, because that can show us some of the problems that can be caused by leukemia.
And the most important thing is bone marrow aspiration and biopsy, which is still, unfortunately, absolutely necessary, first to make the diagnosis, and second, to obtain the specimens for those biomarker testing that you mentioned.
Laura Beth:
If a patient relapses, does all of this testing need to be repeated?
Dr. Ravandi:
Unfortunately, yes. And so, when you said all of these testing, actually, again, compared to some other cancers, this is limited testing. Taking blood for the blood tests, and even doing a bone marrow is generally much easier than taking tissue in a colonoscopy for a colon cancer, or doing a biopsy, a lung biopsy in lung cancer, etc.
But yes, they all need to be tested, and actually, we do like to repeat the genetic testing because leukemias are dynamic, and after initial therapy, they may change in ways. They may develop new targets or new molecular changes that may be potentially amenable to new targeted therapies.
Laura Beth:
And is it common for a mutation to appear at a relapse?
Dr. Ravandi:
It is, yes. I mean, I would say it’s – I wouldn’t say it’s common, but it is frequent.
Which Tests Do You Need Before Deciding on an AML Treatment Path?
Which Tests Do You Need Before Deciding on an AML Treatment Path? from Patient Empowerment Network on Vimeo.
Why is it important to ask about biomarker testing for your AML? Find out how test results could reveal more about your AML and may help determine the most effective treatment approach for your individual disease.
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Transcript:
Why do you need biomarker testing before deciding on a treatment plan for your acute myeloid leukemia—also known as AML?
The results may predict how your AML will behave and could indicate that one type of treatment may be more effective than another.
Biomarker testing—also referred to as risk stratification, genetic testing, or molecular testing—identifies specific gene mutations, proteins, chromosomal abnormalities and/or other molecular changes that are unique to your AML.
The results of these tests are used to determine if you have low-risk or high-risk AML to help guide prognosis and to evaluate the goals of treatment.
There are certain biomarkers—such as the FLT3, IDH1 and IDH2 mutations—that could indicate that your AML may respond well to a targeted therapy. There are several FDA-approved targeted therapies—known as inhibitor therapies—which treat patients with these mutations.
Additionally, the identification of other biomarkers—such as TP53, NPM1, or CEBPA mutations, to name a few—may aid in assessing your prognosis, determining a treatment course, or may identify if an allogeneic stem cell transplant may be appropriate. Results of these tests may also suggest that a clinical trial is your best treatment option.
So, how can you Insist on the best care for YOUR AML?
• First, always bring a friend or a loved one to your appointments to help you process information and to take notes.
• Ask your doctor if you have had, or will receive, biomarker testing and how the results may impact your care and treatment plan. Be sure to ask for paper or electronic copies of your important test results.
• Finally, always speak up and ask questions. It’s important that you understand all of the information that you want to know about your AML to help make the best treatment decisions for you. You are your own best advocate, and treating AML is a team approach.
To learn more about your AML and to access tools for self-advocacy, visit powerfulpatients.org/AML.
Understanding Key Tests That Affect AML Treatment Choices
Understanding Key Tests That Affect AML Treatment Choices from Patient Empowerment Network on Vimeo.
For acute myeloid leukemia (AML), test results play a vital role in determining the most appropriate treatment option. Expert Dr. Ellen Ritchie reviews key tests used to pinpoint a patient’s specific AML, how the test results are utilized, and important questions patients should ask their doctor about AML testing.
Dr. Ellen K. Ritchie is assistant professor of medicine and a member of the Leukemia Program at the Weill Cornell Medical College of Cornell University and the New York Presbyterian Hospital. More about Dr. Ritchie, here.
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Transcript:
Katherine:
So, let’s help our audience be clear about basic testing. What tests are necessary to help understand a patient’s specific disease at diagnosis?
Dr. Ritchie:
I mean certainly it’s important to do a physical exam and to find out what the general health of the patient is. In order to evaluate an AML, or any other leukemia, I look at the peripheral blood smear. To look at what I think the type of leukemia might be that I am dealing with. There are some leukemias that have particular way that they look like acute promyelocytic leukemia for which there is a designated therapy which works.
And you can tell that just by looking at a peripheral blood slide. The next test is always a bone marrow biopsy. Patients are not delighted that that is a test, but it is a test that can be done in the office, usually within 15 to 20 minutes. And that test gives us a lot of information. It gives us information about what type of AML it is, what are the markers on the outside of the cell, it gives us information about the chromosomes inside the leukemia cell. Are there missing chromosomes, or rearranged chromosomes? And if there are, that can be very relevant to the prognosis. And lastly, it’s sent for a particular mutations or markers. So, we look for IDH3 mutations, we look for FLT3 mutations, we look for IDH1 and IDH2 mutations, and we do an entire myeloid panel. Which is about 44/45 genes that are most commonly mutated in patients with AML. So that’s the initial work-up for any AML patient.
Katherine:
You mentioned markers, Dr. Ritchie. What is genomic, or biomarker testing?
Dr. Ritchie:
So, we’re looking really at most specifically at mutations inside individual genes that might be in your leukemia cell. So, there are some mutations actually that confer a better prognosis. Like NPM1 or CEPBA, those can be more positive type of prognosis than some of the others.
But we’re also looking for markers that might be targetable with certain therapies that we have. So, if you have a FLT3 ITD or TKD, we actually have particular drugs which can target those particular mutations. There are also drugs that are FDA approved to treat IDH1 and IDH2 mutations.
There are certain mutations that have a relatively poor prognosis, like TP53 for which there are clinical trials which are available, which specifically are meant to target patients who have those sorts of mutations. And there’re other clinical trials using the FDA-approved drugs that I just mentioned, for FLT3, for IDH1 and IDH2 and combining it with other agents to try and improve outcome in AML patients.
Katherine:
Some patients may not know if they’ve received these important tests, so what key questions should they be asking their physician about testing?
Dr. Ritchie:
So, physicians, they – financial coverage of the mutational testing is not uniform across the country and across insurances. So, Medicare and different Medicare insurances and some of the private insurances all vary in their coverage.
So, in my clinic, I am asking – I prefer the test that we do in house at Cornell. But it’s important that I ask, what will their insurance cover. And make sure that I send the appropriate testing that will be covered by insurance. There are some insurances that will not cover this type of testing. So, it is a real question for the patient, when you go to see the doctor to say, are you going to do mutational NGS testing?
And, will my insurance cover this? Hopefully most – if Medicare adopts the coverage of these types of mutational testing, it’s often true that private insurance will eventually pick this up. But it’s a murky field, and it’s really important to talk to your doctor about this. The cost of the bone marrow biopsy, and the chromosomal evaluation is nearly always covered by insurance.
What Key Tests Do You Need Before Choosing an AML Treatment?
What Key Tests Do You Need Before Choosing an AML Treatment? from Patient Empowerment Network on Vimeo.
How do test results influence treatment choices for AML? Dr. Eunice Wang shares information about essential testing and explains how results aid in determining the best personalized treatment option for each patient.
Dr. Eunice Wang is the Chief of the Leukemia Service and Professor of Oncology at the Roswell Park Comprehensive Cancer Center in Buffalo, New York. Learn more about Dr. Wang, here.
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Transcript:
Katherine:
What is the role of testing when deciding on treatment for AML?
Dr. Wang:
Testing is essential in us selecting and determining the best personalized treatment option for each individual patient. As you know, AML is an aggressive hematologic malignancy and can be devastating, both in its life-threatening nature and in its rapidity and the need for a rapid diagnosis. Testing, including both pathology results as well as protein marker testing, and, importantly in this day and age, DNA and RNA testing is essential because we have numerous different treatment options that could be available to the patient if their particular disease biology matches with the targeted therapies that we have.
So, as you may or may not know, since 2017, we’ve had eight or nine different therapies approved for AML, and this is a bonanza of options, some of which are only for specific biological subsets, and some even for specific patients, such as those above the age of 75. So, doing that testing, particularly that genetic testing, is important both in establishing the diagnosis and determining whether there is less toxic, more targeted, personalized treatment approaches, some of which involve low-dose chemo or even pills available to the individual patient.
Katherine:
You’ve answered this, in part, but which tests are essential following an AML diagnosis?
Dr. Wang:
I think all of them are essential, but in this day and age, for the selection of targeted therapy, it really is the mutational testing, which is looking at the RNA of the tumor cells and determining whether that has been altered in allowing the cells to express abnormal proteins. For standard chemotherapy, we also use DNA testing, which is looking at the different chromosomes and seeing whether there’s breakages or what we call translocations, pieces of chromosomes that have been swapped. That DNA chromosome information can give us some insight into prognosis and therapy response.
So, nowadays, it’s not just determining that you have acute leukemia, but looking at the specific DNA and RNA changes, and I have to say that this is a disease that we’re really not seeing any RNA or mutational changes occurring in more than 20 percent or 30 percent of patients. So all of the mutations that we see that could be impactful really don’t occur in more than 20 percent or 30 percent, and could only occur in five or one percent.
So, really, personalizing an individual patient’s disease, both for the disease biology as well as the person that’s getting the chemotherapy or the diagnosis, is really, really important.
Katherine:
Yeah. Let’s define a few terms that are often confusing for patients. What are biomarkers?
Dr. Wang:
Biomarkers are either proteins or expression levels on the cancer cells that can serve to tell us information about the biology of the disease. Okay, so, for example, if you have evidence of residual tumor proteins in your blood, that could be a marker, for example, of minimal residual disease, okay? And, that can tell you maybe one in a million cells have that biomarker, and then you can tell that those one-in-a-million cells are leukemia cells.
So, they’re any marker that we’re using that’s specific for the tumor that can help us in predicting or finding or locating or determining if a tumor would respond to a certain therapy.
Katherine:
What is biomarker testing?
Dr. Wang:
Biomarker testing can be done in many ways. For example, biomarker testing is drawing a sample from the patient and evaluating a marker that we think is going to predict for the disease type.
So, for example, in some cancers, we don’t want to biopsy the lung mass or the tumor mass every single time to see whether it’s shrinking, or getting smaller, or responding. So, in those patients, sometimes we’ll draw a blood sample, and we’ll look for a surrogate marker – some protein that’s expressed in the blood or some DNA or RNA in the blood that is a surrogate or a marker of the tumor so you don’t have to directly biopsy it.
In acute myeloid leukemia, we are looking for – like I said – particular cells in the blood that have particular proteins, and we measure those rather than going ahead and doing that bone marrow biopsy or biopsying those tumors. So, generally, in leukemia, it involves drawing blood samples – that’s the most common; it is a bloodborne disease.
Sometimes, we actually have to go into the bone marrow and do a bone marrow sample, but those biomarkers, as I said, can really improve our ability to detect very, very low levels of disease. So, for example, using a conventional bone marrow biopsy, we can only really detect 1 out of 200 cancer cells by normal – just by visual looking at, but by measuring biomarkers and mutations and other abnormal proteins, we can improve that to 1 in 100,000 cells.
So, really, these biomarkers are very sensitive and important because we want to detect the disease at a point where it’s very, very low. We don’t want to wait until the disease gets very advanced, in which case we think our therapies are less effective.
Katherine:
What is a genetic mutation?
Dr. Wang:
A genetic mutation is a mutation that occurs in the RNA of a cancer cell. That RNA dam – RNA aberration or abnormality does lead to different RNA – what we call transcript levels that lead to abnormal proteins.
Those proteins function in the cells to make a cell a cancer cell, okay? So, all cancer cells start out as normal cells, and as they acquire a mutation, they become a little less normal, and they start acquiring multiple mutations, and some of these mutations occur without DNA changes, some of them occur with DNA changes. And as these abnormalities occur, the cell gets more and more dysfunctional, and eventually, it starts becoming almost evil-ish.
It starts acquiring behaviors that are not normal, and then it starts to grow out of control, and that unchecked growth really is the end result of potentially many mutations occurring over time to drive that cell into becoming a cancer cell, and we call that process transformation, transforming from a normal, healthy-looking cell into almost a monstrous, cancer-like cell.
Katherine:
How do biomarkers affect AML treatment choices?
Dr. Wang:
So, those biomarkers, as I talked about, those mutations can determine what type of therapy patients can have. For example, up to 25 percent or 37 percent of newly diagnosed AML patients will have leukemia cells that carry the biomarker or the mutation in a gene called FLT3, or “flit.”
Those FLT3 cells can be inhibited by specific targeted therapies, including a drug called gilteritinib (Xospata), which is a pill which blocks mutant FLT3 expressed by AML cells. So, we’ve demonstrated, actually, in a randomized clinical trial that patients who have relapsed or recurrent AML who carry cells that have that biomarker – that FLT3 mutation – will actually do better if they take a daily pill – a FLT3 inhibitor – every single day for treatment of their aggressive acute myeloid leukemia than if we gave them low- or even high-dose chemotherapy in the hospital for four to six weeks.
So, that’s the power of those targeted therapies. Because the biomarker is telling you that there’s a sensitivity of that cancer cell to a specific blockage of that pathway, that can really dramatically change the course.
That is where the importance and the power of those biomarkers really goes into play. In the past, patients who had acute myeloid leukemia with FLT3 mutations did poorly with chemotherapy and had disease that came back even after multiple rounds of that intensive chemotherapy. The fact that we can give a pill and people could do better or even go to a bone marrow transplant off treatment with the pill is pretty remarkable.
How Molecular Testing Has Transformed AML Treatment Options
How Molecular Testing Has Transformed AML Treatment Options from Patient Empowerment Network on Vimeo.
How has molecular testing impacted approaches to acute myeloid leukemia (AML) therapy? Dr. David Sallman explains how molecular testing has transformed AML care, including a discussion of risk assessment and the role of next-generation sequencing (NGS) in tailoring care for each patient.
Dr. David Sallman is an Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center where he specializes in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN). Learn more about Dr. Sallman, here.
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Transcript:
Katherine:
How has molecular testing changed the landscape of therapy for AML?
Dr. Sallman:
Yeah, it’s really transformed it, and it’s really a constantly evolving paradigm. We have updated classifications; most people utilizing the ELN system.
So, based on both cytogenetic and molecular factors, you can ultimately go into good risk, intermediate risk, adverse risk. In general, for fit patients for good risk, we focus on curative intent, ideally with chemotherapy alone. For intermediate and adverse, typically we’re incorporating allogeneic stem cell transplant. So, that’s one of the main things that really guides treatment really from the beginning and throughout.
Then, I think really where it’s evolving is personalized therapy. So, it’s really not a one-size-fits-all treatment paradigm, it’s you have mutation A, B, you’re this age, this fitness, and we put all those things together to ideally come up with the best treatment plan for the patient.
Katherine:
Is molecular testing standard following an AML diagnosis or is this something that patients should ask for?
Dr. Sallman:
It definitely should be standard and I think the challenge is when you say the word “molecular,” it means lots of things to different people. I think in the community, as targeted medications were first approved, so this was with FLT3 inhibitors, subsequently IDH1 and IDH2 inhibitors, I think people are realizing yes, we have to send these sequencing panels, but there’s a potpourri of choices from a lot of different commercial vendors.
Really the key and one of the main messages we try to get across is you really have to assess for both FLT3 as well as really a comprehensive next-gen sequencing panel in order to cover all of the relevant genes at diagnosis and likely at other time points such as relapsed or refractory disease.
So, there’s no question, it’s standard, although unfortunately, it’s still not uncommon where the comprehensive panels are not sent and you’re left with somewhat not a complete picture for your patients. Since we’re personalizing everything, it’s really quite critical to have these data.
Katherine:
Yeah. How does inhibitor therapy work to treat AML?
Dr. Sallman:
So, you have a gene that turns on and turns off as we go, but with the mutation, it’s basically turned on all the time. Then, you can have targeted pills that basically turn it off. Most commonly this is done, there’s the active
or energy site for these different genes, and so these therapies can really specifically block that. I wouldn’t say that’s the only mechanism. There are IDH1 and IDH2 inhibitors and they’re very specific for those mutations. Each mutation may have a little bit different end biology. In general, you have mutation A, and we’re going to turn it off with drug that inhibits A.
Advocating for Key AML Testing: Advice From an Expert
Advocating for Key AML Testing: Advice From an Expert from Patient Empowerment Network on Vimeo.
Dr. Hetty Carraway, an AML specialist at Cleveland Clinic, shares advice on advocating for yourself when diagnosed with AML, underscoring the importance of asking questions, and including your caregiver as part of the conversation.
Dr. Hetty Carraway is Director of the Leukemia Program at Cleveland Clinic. Dr. Carraway cares for patients with acute leukemia and bone marrow failure states. Learn more about Dr. Carraway, here.
Related Resources:
Transcript:
Katherine:
What advice do you have for patients when it comes to asking for appropriate testing and speaking up in their own care?
Dr. Carraway:
This is so important. I think patients are leery to stir the pot or be difficult. I think coming from a place of inquiry, teach me about this, that, or the other thing, help me understand this, that, or the other thing – I would like you to show me why this decision or talk with me about why this decision versus another decision might be better for me compared to somebody else.
I can’t underscore the importance of advocating for yourself and asking questions about why am I getting this drug? What are the side effects to this drug? What is my prognosis? What is different about my case versus somebody else’s situation? How do I best prepare myself in getting ready for the therapy that I’m about to go through?
Those are all important questions that patients should ask. They should certainly have people, if possible in their family be advocates for them. I welcome that, and I think that that’s a really important part of going through this type of therapy for any patient. Your physician should welcome having your involvement in that. Don’t be shy about that. It’s your health, and any investment in that the most important people in that is inclusive of you and your caregivers. They should be a welcome part of the team.
Essential Testing in AML: How Results Impact Care & Treatment Choices
Essential Testing in AML: How Results Impact Care & Treatment Choices from Patient Empowerment Network on Vimeo.
What tests should follow an AML diagnosis and why? Dr. Hetty Carraway, an AML specialist of Cleveland Clinic, reviews the essential testing for patients with AML and explains how those test results may inform treatment decisions.
Dr. Hetty Carraway is Director of the Leukemia Program at Cleveland Clinic. Dr. Carraway cares for patients with acute leukemia and bone marrow failure states. Learn more about Dr. Carraway, here.
Related Resources:
What Is the Patient’s Role in Making AML Treatment Decisions? |
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Transcript:
Katherine:
Hello, and welcome. I’m Katherine Banwell. Today, we’ll discuss how you can be proactive by insisting on better AML care and personalized treatment options. Joining me is Dr. Hetty Carraway.
Welcome, Dr. Carraway. Would you please introduce yourself?
Dr. Carraway:
Hi. My name is Dr. Hetty Carraway. I’m one of the physicians at the Cleveland Clinic. I work as the Director of the Leukemia Program, and I spend most of my time caring for patients with acute leukemia and bone marrow failure states.
Katherine:
Thank you. Let’s start with the basics. What essential testing should AML patients undergo following a diagnosis?
Dr. Carraway:
This is a pretty standard workup for patients that have this diagnosis of acute leukemia.
For most of our patients we always evaluate with a peripheral blood count including a complete blood count with differential, typically a comprehensive metabolic panel, and looking at a test called a uric acid, which looks at the cell turnover and the cellular debris in terms of the burden on the kidney. We often will get a bone marrow biopsy with aspirate for patients, and in the diagnosis of leukemia typically that’s already been done.
There are tests that are sent off of that aspirate called a test for chromosomes, whether it’s comprehensive cytogenetics or FISH, for fluorescence in situ hybridization. We’re often testing using a study called NGS or next generation sequencing looking for specific mutations of genes known to be important in the pathogenesis of leukemia.
Furthermore, we often get a test called flow cytometry from that aspirate looking at the markers on top of the leukemia cells that help us to identify the blast population. So, I would say those by and large are the tests in the bone marrow biopsy that we get, which are innumerable and detailed.
They often take some time to get back, so at the time of the diagnosis patients know that they have a diagnosis of leukemia, but those additional chromosome tests or mutation testing that can take up to two weeks if not longer to get back. And so, it’s important to follow up on that information later on and say, has that testing come back? If so, how does that change any of what the decisions are moving forward?
Katherine:
Genetic testing can often be confused with molecular testing. What’s the difference between the two, and why should patients undergo the testing?
Dr. Carraway:
The chromosome testing and the mutational testing help us to really classify the risk in terms of the leukemia itself, whether or not that leukemia is responsive to chemotherapy alone, or if it means that there’s a higher likelihood of that leukemia not being controlled with leukemia only.
In that setting, we often then move towards transplant for curative intent in addition to the chemotherapy. The reasons to get the information is to really help us better tailor the therapy for each individual patient. That information really does help us guide not only the upfront therapy for some patients but even the long-term therapy. It can be incredibly overwhelming to have too much information at the get-go, so in some senses it’s better to have these pieces as they unfold over time.
For other patients, they want to know what exactly the plan is going to be A to Z from day one. That is of course more challenging now that it just takes time to get this information. I think what they need to know is that we’re working hard to get that information.
As soon as we get it, we don’t hold back. We reveal and share that information and come together to say, this is what this data or information means, and these are some of the choices that we either recommend that you consider, and these are the risks and benefits to those considerations.
Katherine:
Let’s look at something that is similar to what you’ve just been talking about. How do test results impact treatment and overall care?
Dr. Carraway:
They really can. When you asked me how come chromosome or genetic information is different than mutational information, the chromosomes can help us to figure out where patients land in terms of prognosis. That information is different than the mutational testing. Both of those pieces can help us figure that out.
The mutational test, I will tell you, does help us figure out are there targets on the leukemia that allow us to use therapy that’s directed to that mutation. The key example I’ll give is a mutation in a gene called FLT3. That particular mutation has an agent now that is F.D.A. approved called Midostaurin, and so once we know that a leukemia harbors a FLT3 mutation we often add a drug called Midostaurin to the backbone therapy that is used for patients.
Now, that’s important, and now there are more and more genes that when mutated we have novel therapies that direct against that specific tag that’s on the leukemia and helps to improve eradication of the disease or control of the disease if you will.
That’s different than the genetic information when we’re looking at chromosomal changes that may allow us to say in the rare instances of favorable cytogenetics like a translocation of chromosome 15 and 17 consistent with APL, the treatment for that type of leukemia, acute promyelocytic leukemia, is very different than what we do for the majority of other leukemias.
The prognosis for that leukemia is also very different. It helps to tailor the regimens, and it helps to select specific therapy that may be helpful to each individual patient.
Katherine:
Dr. Carraway, you just mentioned FLT3. Would you tell us about the common mutations in AML and how these may impact treatment options?
Dr. Carraway:
There’s a multitude of mutations that we’re now following in patients. The way that we follow them is by doing this next generation sequencing test at the upfront time at diagnosis.
The reason why we’re doing that is because those mutations can regress with therapy, or they can progress where you gain additional mutations that happen as the disease progresses. Even if it’s responding to therapy or as it loses response to therapy and reemerges, it may reemerge with different mutations. As a result of that, it may change what therapy we select. Our ability at this point in being to recommend exactly at what time points we are checking the next generation sequencing we’re still learning right now as to what are the key times to do that testing.
In general, most institutions are doing that next generation sequencing at the time of diagnosis, and then also for some patients before they go to bone marrow transplant and even after bone marrow transplant.
For some of those patients that unfortunately relapse, we’re also making sure to retest the next generation sequencing mutation testing to see are there new mutations that have come about that weren’t there before?
Katherine:
I understand there’s something called IDH.
Dr. Carraway:
You were also asking about what other mutations besides FLT3 happen in patients with AML. FLT3 is one such mutation. NPM1 is another mutation that often it frequents patients that have AML. Those two mutations happen in about 30 percent of patients with AML. There are other mutations such as DNMT3A, ASXL1, and TET2 that we typically see in patients with MDS or even a pre-leukemia state called CHIP. For other patients, we have mutations that are targetable like IDH1 or IDH2.
Those two mutations happen in probably 10 percent to 15 percent of patients diagnosed with AML. Why are those important? They’re important because we have oral medications that are pills that patients can take. In the relapse setting for many patients after induction or intensive chemotherapy, they can use these oral therapies to try and control their leukemia. These are pretty exciting.
All of these oral therapies have been approved in the last two to three years in the space of leukemia, so it’s been a game-changer in terms of identifying these mutations and then identifying drugs that target those mutations. It’s really changed the landscape for patients with AML. It’s new information, and that’s why as patients you want to hear about this so you know what questions to ask and you know, can you tell me, am I a candidate for one of these oral medications that is now available for patients with AML?
Katherine:
Dr. Carraway, thanks so much for joining us today.
Dr. Carraway:
Thank you for the opportunity to be here.
Katherine:
And thank you to our audience. I’m Katherine Banwell.
