https://www.onclive.com/insights/therapeutic-agents-aml-cll/mutational-drivers-of-acute-myeloid-leukemia
Mutational Drivers of Acute Myeloid Leukemia

Panelists: Matthew S. Davids, MD, MMSc Dana-Farber Cancer Institute; Naval G. Daver, MD The University of Texas MD Anderson Cancer Center; Daniel A. Pollyea, MD, MS University of Colorado School of Medicine



Transcript: 

Naval G. Daver, MD:
We have identified a number of biological mutations that seem to be drivers in acute myeloid leukemia. These include FLT3, IDH1, IDH2, and others now, such as the XL1 TP53. What we’ve learned is that these play a major role in prognosis. So the presence or absence of these at new diagnosis and at relapse will let us know whether a patient has a good chance of long-term remission, whether he would need an allogeneic stem cell transplant or not. And then, more important, now we have drugs that target these mutations, especially FLT3, IDH1, and IDH2, very effectively and are able to improve the response rates, as well as duration of response and overall survival.

So the issue that we have, though, is these biological mutations do not work independently. They seem to work with each other, and that’s where combination therapy is important. Because even if you’re targeting 1 biological driver like FLT3, it’s unlikely you’re going to get a very long-term remission. But, if you combine that with low-dose therapy, azacitidine, or others, then you may be blocking the other pathways, and that’s why we’re seeing much better responses in survival with the combos targeting biological agents.

The molecular testing should be done for sure at diagnosis. I think this is the most important time point. The specific mutations that we would recommend testing for are FLT3, IDH1, IDH2, and then other things that are not mutations per se but are important treatment decisions. What we call chromosome analysis for 15;17 APL [acute promyelocytic leukemia], because they have a different treatment, and then chromosome analysis for inversion 16, 8;21, what we call core binding factor leukemia, because they benefit significantly from the addition of Mylotarg and have good survival. So you really have 5 different group molecular cytogenetics in the diagnosis, which have different treatments, and adding that particular treatment improves survival significantly.

At relapse, we routinely, being a large academic center, do test for the full molecular panel of 81 genes. In the community, as these drugs are becoming available, I would strongly recommend checking for at least IDH1, IDH2, and FLT3. And IDH1 and IDH2 obviously are important because if a patient is failing induction, 3 + 7, Vidaza, you could give them an IDH inhibitor and have a 35% to 40% chance of response, CR [complete remission], CRh [CR with partial hematologic recovery], which is equal to or better than what you would get in chemotherapy.

And the FLT3 is especially important to do with relapse, because even if you have a FLT3 positive at diagnosis and you give them induction with FLT3 inhibitor midostaurin at relapse, about 35% to 40% of them will lose the FLT3 and they may not be candidates for the FLT3 inhibition such as quizartinib and gilteritinib, and vice versa: There may be people who get 3 + 7 and did not have a FLT3 baseline and acquire or had an emergence of a FLT3 at relapse, and they may now become candidates for quizartinib, gilteritinib. So I would say the FLT3 IDH1-2 should be tested at relapse again, even if they were or were not tested at diagnosis.

So the routine turnaround time that we’re getting for our NGS [next-generation sequencing] molecular panel is about 72 hours for the important mutations that come on the first panel, which include the FLT3; IDH1, 2; NPM1; CEBPA. In parallel to the NGS testing, we’re also rushing chromosome testing with what we call FISH [fluorescence in situ hybridization], or FISH cytogenetic analysis that looks for translocation 15;17 that would diagnose APL. We get those results in about 24 hours, in fact, because we want to know the APL information very quickly and treat it, since it’s very curable if we treat it early and avoid early mortality.

And then we also run a FISH chromosome probe for inversion 16, 8;21, and these are core-binding factors, and we get that also in 24 to 48 hours. So in 72 hours, we have this critical first stream of information, whether it’s coming from FISH chromosome or from NGS, to help us select which of these 5 groups this patient will fall into—FLT3, IDH, core-binding factor, APL, or others.

Daniel A. Pollyea, MD, MS: FLT3 mutations are some of the most common mutations that exist in AML, and we’ve known about them for quite a while, going back 20 years now. And what we know is that they are associated with worse outcomes with patients who develop these with their AML. We think that that’s mostly because it causes the disease to become very proliferative. And while that doesn’t usually interfere with their ability to get into an initial remission, FLT3 has a very negative prognostic significance mostly because of the high risk of relapse and disease progression. And it…has been historically a really terrible subgroup of AML patients that have had really, really poor outcomes.

FLT3 mutations occur in probably 20% to 30% of AML patients. They’re a little bit more common in younger patients or in patients with de novo disease, patients with a normal karyotype. The prognosis associated with having a FLT3 mutation in AML is very poor. Patients tend to relapse and die from their disease.

There are 2 main mutations that we’re aware of that can occur in the FLT3 gene. The more common is the internal tandem duplication, which causes disease to be very proliferative and has a known poor outcome associated with it. You can also develop mutations in the tyrosine kinase domain of the gene, and the prognostic significance of those are a little bit less clear, at least in the de novo setting. We do know that in the relapsed refractory setting—in particular, in the face of patients who have been on a FLT3 inhibitor—that oftentimes a mechanism of resistance occurs through mutations in the tyrosine kinase domain mutation, and so those have a very poor adverse consequence as a result of that.

I think the use of FLT3 inhibitors in clinical practice is a very exciting new topic. Currently, we use midostaurin with intensive induction chemotherapy for fit patients who have a FLT3 inhibitor…or FLT3 mutation at the time of diagnosis, and that’s really the standard of care. Whether or how some of the more specific FLT3 inhibitors will work their way into the…algorithms remains to be seen, but I think most people have an expectation that that will allow for some increased benefit.

On the relapse side, I think the role for a FLT3 inhibitor is…there are a few. We may find that they work best in combination with other therapies. We may find that they are reliable bridges to a transplant and, therefore, allow for a patient to get to a cure, which would not otherwise be possible. But when FLT3 inhibitors are used as single agents in the relapsed-refractory setting and there’s no plan to bridge to a transplant, then I think that we have to be realistic about expectations. And those expectations are that, yes, the majority may be…patients that can get into a remission, that those remissions will be brief, and everybody should understand that before undergoing…that path…because you know expectations really need to be realistic.


Transcript Edited for Clarity 
 
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