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Testing for FLT3 Mutations in the Community Setting of AML

Insights From: Richard F. Schlenk, MD, University of Ulm; Harry Erba, MD PhD, University of Alabama ; Naval G. Daver, MD, MD Anderson Cancer Center
Published: Monday, Oct 15, 2018



Transcript: 

Harry Erba, MD, PhD:
The addition of mutational analysis at the time of diagnosis in acute myeloid leukemia adds cost to the care of these patients and may even delay therapy if you’re considering acting upon it. Until recently, the major benefit of having this information was prognostication. Based on this, the College of American Pathologists and American Society of Hematology put out guidelines in March of 2017, strongly recommending FLT3 ITD [internal tandem duplication] mutation analysis at the time of diagnosis. I believe the reason for this is mostly around the prognostic significance of that information; however, we now have a drug that is approved for patients with both FLT3 ITD and TKD [tyrosine kinase domain]-mutated disease, midostaurin. This should be broadened to a strong recommendation for FLT3 mutational analysis at the time of initial diagnosis.

All other mutational analysis will add prognostic information and is not needed as quickly as the FLT3 analysis is, at least at the time of initial presentation. There’s much debate in the literature regarding how these mutations may interact, things that we don’t yet have standardized such as the relationship between allelic ratios and allelic frequencies of FLT3, the ultimate outcomes, and how the different genetic changes may interact in a patient. So there is still quite a bit of uncertainty, specifically regarding how we can use information to improve on the prognosis and act on those markers to improve the outcome of these patients.

However, since it is prognostically important, we’ve been using these features to generally consider patients for allogeneic stem cell transplantation in first-remission if they have high-risk features. Now that we have an FDA-approved drug for the FLT3-mutated patients, I think there should be quite a bit of emphasis on having this done for all patients with acute myeloid leukemia. Again, I will reiterate that the FLT3 PCR [polymerase chain reaction] test should be ordered at the time of diagnosis because this analysis will [provide results] quicker than a next-generation sequencing [NGS] panel, which may in fact miss the presence of an FLT3 ITD mutation based on the technology that is used.

Naval G. Daver, MD: In the community, I think that there are now sufficient data to say that the FLT3 inhibitors are no longer in the research arena and that these are either approved or close to approval. In the lectures and in the recommendations we give to community doctors, we recommend checking for many mutations in newly diagnosed AML. But the most important of those are FLT3, IDH1 [isocitrate dehydrogenase 1] and 2, TP53 [tumor protein p53], and NPM1 [nucleophosmin]. And indeed, the NCCN [National Comprehensive Cancer Network] guidelines as well as the ELN [European LeukemiaNet] guidelines now routinely recommend checking for these mutations. Almost all insurance carriers that I’m aware of cover testing for these mutations.  We think that this mutational testing should be done, and done very quickly, because now we actually have treatments that can impact the outcome. We need to have these results in real-time. There are a number of labs that are doing this testing and are able to give a quick turnaround.

One of the things we’ve learned is often the physician or his staff—PAs [physician assistants], nurses—have to call the send-out lab, whether it’s Foundation Medicine or NeoGenomics. There are a lot of them. If you call and say, “Look, I am considering this patient for an FLT3 inhibitor; I need to have results in 7 or 8 days,” almost all the labs are actually able to act on it and give the results. However, if you just send out a standard panel, they often think this may be for the subsequent relapse or just as a didactic research activity, and they may take up to 14 to 20 days. I think this is a very important point with community doctors. You need to call and get the FLT3, IDH, or NPM1 mutation testing.

If you have a patient who has a very high white count or proliferative disease, one should already be thinking that there is a higher chance that this will be an FLT3-mutated patient because this is how they present. So, especially in that setting, I think it does make sense to try and wait. For the last 30 to 40 years, there has been a dogma that AML is acute, severe and exigent; but the sun should not set on AML. You have to use chemotherapy. If you speak to almost all the experts across the country, we’ve actually changed our mind on this. We do think that earlier treatment is good, but the benefit of adding targeted therapy is paramount. If one had to choose whether you’re going to add an FLT3 inhibitor, an IDH inhibitor, or Mylotarg [gemtuzumab ozogamicin] in the appropriate settings versus treating it quickly and not adding those, there are a lot of data to show that the addition of the appropriate agent is more cost-efficient.

We’re not saying you can wait for every single AML case because I don’t think all AMLs come in 1 flavor. If you get a patient with a white count of 120,000, 130,000, he’s unstable, and he has hypoxia or shortness of breath and fevers, you have to go and start the treatment. Even on peripheral blood, you can send him off for testing. When you get the results back in 7 or 8 days, you can add the FLT3 inhibitor to the situation. The key is to get the testing done, and I think that’s what we’re really recommending in the frontline setting for FLT3 mutations.

Harry Erba, MD, PhD: From a clinical standpoint, the only mutational analysis that must be repeated at the time of relapse would be mutational analysis for IDH1 and IDH2, because we now have 2 FDA-approved drugs. For the IDH1-mutated patients, there’s ivosidenib; for the IDH2-mutated patients, there’s enasidenib. Outside of those therapeutic targets, there are no approved drugs for patients with relapsed/refractory acute myeloid leukemia. Since the outcomes of these patients with relapsed/refractory AML are so dismal, especially with practicing in an academic environment, these patients should be considered for clinical trials that repeat the entire mutational profile.

Why does it need to be repeated? Well, we know that the genesis of acute myeloid leukemia is a multistage process with mutations occurring often in sequence, resulting in the phenotype of acute myeloid leukemia. When the patient achieves a remission, some of those clones that have developed may also go into remission; but others may persist and generate, causing new clones to populate. Incidentally, the mutational profile at relapse may not be identical to that at initial presentation. In fact, for FLT3, it is estimated that about 5% of the time, a patient who is positive for an FLT3 mutation at diagnosis will be negative at relapse and vice versa. If they were negative at diagnosis, they may become positive at the time of relapse.


Transcript Edited for Clarity
 
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Transcript: 

Harry Erba, MD, PhD:
The addition of mutational analysis at the time of diagnosis in acute myeloid leukemia adds cost to the care of these patients and may even delay therapy if you’re considering acting upon it. Until recently, the major benefit of having this information was prognostication. Based on this, the College of American Pathologists and American Society of Hematology put out guidelines in March of 2017, strongly recommending FLT3 ITD [internal tandem duplication] mutation analysis at the time of diagnosis. I believe the reason for this is mostly around the prognostic significance of that information; however, we now have a drug that is approved for patients with both FLT3 ITD and TKD [tyrosine kinase domain]-mutated disease, midostaurin. This should be broadened to a strong recommendation for FLT3 mutational analysis at the time of initial diagnosis.

All other mutational analysis will add prognostic information and is not needed as quickly as the FLT3 analysis is, at least at the time of initial presentation. There’s much debate in the literature regarding how these mutations may interact, things that we don’t yet have standardized such as the relationship between allelic ratios and allelic frequencies of FLT3, the ultimate outcomes, and how the different genetic changes may interact in a patient. So there is still quite a bit of uncertainty, specifically regarding how we can use information to improve on the prognosis and act on those markers to improve the outcome of these patients.

However, since it is prognostically important, we’ve been using these features to generally consider patients for allogeneic stem cell transplantation in first-remission if they have high-risk features. Now that we have an FDA-approved drug for the FLT3-mutated patients, I think there should be quite a bit of emphasis on having this done for all patients with acute myeloid leukemia. Again, I will reiterate that the FLT3 PCR [polymerase chain reaction] test should be ordered at the time of diagnosis because this analysis will [provide results] quicker than a next-generation sequencing [NGS] panel, which may in fact miss the presence of an FLT3 ITD mutation based on the technology that is used.

Naval G. Daver, MD: In the community, I think that there are now sufficient data to say that the FLT3 inhibitors are no longer in the research arena and that these are either approved or close to approval. In the lectures and in the recommendations we give to community doctors, we recommend checking for many mutations in newly diagnosed AML. But the most important of those are FLT3, IDH1 [isocitrate dehydrogenase 1] and 2, TP53 [tumor protein p53], and NPM1 [nucleophosmin]. And indeed, the NCCN [National Comprehensive Cancer Network] guidelines as well as the ELN [European LeukemiaNet] guidelines now routinely recommend checking for these mutations. Almost all insurance carriers that I’m aware of cover testing for these mutations.  We think that this mutational testing should be done, and done very quickly, because now we actually have treatments that can impact the outcome. We need to have these results in real-time. There are a number of labs that are doing this testing and are able to give a quick turnaround.

One of the things we’ve learned is often the physician or his staff—PAs [physician assistants], nurses—have to call the send-out lab, whether it’s Foundation Medicine or NeoGenomics. There are a lot of them. If you call and say, “Look, I am considering this patient for an FLT3 inhibitor; I need to have results in 7 or 8 days,” almost all the labs are actually able to act on it and give the results. However, if you just send out a standard panel, they often think this may be for the subsequent relapse or just as a didactic research activity, and they may take up to 14 to 20 days. I think this is a very important point with community doctors. You need to call and get the FLT3, IDH, or NPM1 mutation testing.

If you have a patient who has a very high white count or proliferative disease, one should already be thinking that there is a higher chance that this will be an FLT3-mutated patient because this is how they present. So, especially in that setting, I think it does make sense to try and wait. For the last 30 to 40 years, there has been a dogma that AML is acute, severe and exigent; but the sun should not set on AML. You have to use chemotherapy. If you speak to almost all the experts across the country, we’ve actually changed our mind on this. We do think that earlier treatment is good, but the benefit of adding targeted therapy is paramount. If one had to choose whether you’re going to add an FLT3 inhibitor, an IDH inhibitor, or Mylotarg [gemtuzumab ozogamicin] in the appropriate settings versus treating it quickly and not adding those, there are a lot of data to show that the addition of the appropriate agent is more cost-efficient.

We’re not saying you can wait for every single AML case because I don’t think all AMLs come in 1 flavor. If you get a patient with a white count of 120,000, 130,000, he’s unstable, and he has hypoxia or shortness of breath and fevers, you have to go and start the treatment. Even on peripheral blood, you can send him off for testing. When you get the results back in 7 or 8 days, you can add the FLT3 inhibitor to the situation. The key is to get the testing done, and I think that’s what we’re really recommending in the frontline setting for FLT3 mutations.

Harry Erba, MD, PhD: From a clinical standpoint, the only mutational analysis that must be repeated at the time of relapse would be mutational analysis for IDH1 and IDH2, because we now have 2 FDA-approved drugs. For the IDH1-mutated patients, there’s ivosidenib; for the IDH2-mutated patients, there’s enasidenib. Outside of those therapeutic targets, there are no approved drugs for patients with relapsed/refractory acute myeloid leukemia. Since the outcomes of these patients with relapsed/refractory AML are so dismal, especially with practicing in an academic environment, these patients should be considered for clinical trials that repeat the entire mutational profile.

Why does it need to be repeated? Well, we know that the genesis of acute myeloid leukemia is a multistage process with mutations occurring often in sequence, resulting in the phenotype of acute myeloid leukemia. When the patient achieves a remission, some of those clones that have developed may also go into remission; but others may persist and generate, causing new clones to populate. Incidentally, the mutational profile at relapse may not be identical to that at initial presentation. In fact, for FLT3, it is estimated that about 5% of the time, a patient who is positive for an FLT3 mutation at diagnosis will be negative at relapse and vice versa. If they were negative at diagnosis, they may become positive at the time of relapse.


Transcript Edited for Clarity
 
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