What are the common mutations in AML and how those different mutations affect to treatments?

What are the common mutations in AML and how do those different mutations affect treatment?

What's interesting about acute myeloid leukemia is that there are sort of a fixed number of potential mutations that can develop. So if you think about a different kind of cancer like lung cancer or breast cancer, actually those cancers have so many different mutations. Sometimes a patient will have hundreds of mutations when those cancers develop. In acute myeloid leukemia, we sort of know the genes that are mutated. And typically it's not more than two, three, four genes that end up being mutated.

The most common mutations that we see in patients with acute myeloid leukemia are mutations in a gene called NPM1, or nuclearphosmin. Mutations in a gene called DNA methyltransferase or DNMT3A, mutation in a gene called FLT3, or mutations in genes called IDH1 or IDH2. Those are the most common mutations. Those mutations had both prognostic impact. And they are also able to have specific drugs that target them. And having those specific drugs that target them is what makes them important.

So the mutations that I just talked about, we have drugs that target FLT3. We have a drug, a new drug that targets NPM or that will target NPM1. We have drugs that target IDH1 and IDH2. And we've already seen in clinical trials that when you give these targeted therapies that target these specific gene mutations in combination with chemotherapy, those patients actually do better than if you just give chemotherapy alone.

What is the significance of the FLT3 mutation in AML, and how does it influence treatment choice?

FLT3 mutation in acute myeloid leukemia is very common. It occurs in about 30% of patients with acute myeloid leukemia. And in general, if you are diagnosed with AML with a FLT3 mutation, we used to view it as having that mutation made the chances of going into remission and being cured of being lower than if you didn't have that mutation. Now, what the good news is, is that over the past eight years, there have been a number of drugs that have been developed to target the FLT3 mutation.

So now that we have these drugs, actually having a FLT3 mutation isn't nearly as bad as it was maybe 15 years ago. So there are a number of different drugs. There are two drugs that are used for newly diagnosed acute myeloid leukemia in patients with a FLT3 mutation. One of those is a drug called midostaurin, which is given in combination with chemotherapy. A newer one is called quizartinib, which is also given in combination with chemotherapy. The difference between those two drugs is quizartinib a little bit more potent than midostaurin, but doesn't tackle every single FLT3 mutation. It only tackles the most predominant FLT3 mutation, with chemotherapy for relapsed and refractory acute myeloid leukemia. We have a really, really powerful targeted drug called gilteritinib, which is used as a single agent. So just gilteritinib, for patients with relapsed and refractory AML, that drug works really well. It seems to work better than chemotherapy. So that's become the standard of care for relapsed refractory AML with the FLT3 mutation.

How do mutations like NPM1 or CEBPA influence prognosis in AML?

NPM1 and CEBPA are mutations that, generally speaking, are favorable risk mutations. When a patient is newly diagnosed with acute myeloid leukemia, we stratify that patient into having either favorable risk disease, intermediate risk disease, or adverse or unfavorable risk disease. Those are the same thing. And how we stratify people is completely based on the genetics of their leukemia.

So certain genetic mutations put you into a favorable risk group. Other mutations put you into an unfavorable risk group. Mutations in NPM1 and CEBPA generally put you into a favorable risk group. The one caveat to that is that sometimes you don't only have one mutation. So sometimes if you have an NPM1 mutation with, for example, a FLT3 mutation, you get downgraded from a favorable risk group to an intermediate risk group. Because the FLT3 mutation puts you into a different group.

There's a difference also with NPM1 and CEBPA because what we think about those mutations is that they're very sensitive to chemotherapy. There are some patients with those mutations where we actually think that perhaps you don't need to give them a stem cell transplant in order to cure them. They may be curable with chemotherapy alone.

If you want to learn more about FLT3 mutations and gilteritinib, check out our Know Your Therapy course in the link in the description.