SOHO 2024 | Key considerations for community physicians in the management of secondary AML

The first thing that needs to be spelled out is that secondary AML is a mixed bag of diseases. There is therapy-related AML, which is happening from previous exposure to chemotherapy. And then there’s MDS, CMML, and MPN that then transform to AML. So there are two different scenarios that people can get secondary leukemias from, and the difference is people who do have prior MDS, MPN, and CMML, they have many times have had exposure to hypomethylating agents before they get leukemia. So they’re already kind of having this first-line therapy already done, and a big drug is out of the armamentarium. So it’s important to know these differences.

The second point is to understand that obviously these diseases have a higher chance of having adverse risk cytogenetics and more importantly TP53 mutations, which are known to be very resistant to our current modern drugs, even the ones we have. And we’re going to talk about that a little bit separately. For people who are exposed to prior hypomethylating agents, we really don’t have any good therapies. The best response rates we have is with CPX351 or liposomal daunorubicin and cytarabine, which gives about a response rate of 30% complete remission rate and then the intent is to transplant. Hypomethylating agent and venetoclax as a combination can be used. Sometimes low-dose ARC with venetoclax if you have had a previous exposure to hypomethylating agents could be used. Again, giving responses in the 30 to 40% range. But these are sort of the two or three drugs that are available. And then trying to transplant them but understanding that these people are going to do poorly, and they should really go on clinical trials to achieve a better response.

Now, outside of the prior HMA exposure, if you think about the other secondary, you know, AML. Again, the two drugs that are currently approved and active are CPX351 and HMA/venetoclax, based on whether they’re intensive chemotherapy eligible or not. When we did a retrospective comparison at Cornell, among other institutions, we didn’t find a big difference between CPX351 versus HMA/venetoclax, so you could use them one way or the other. But the point is to get them into remission and try to transplant them. I think a lot of people are not getting transplanted when they get HMA-VEN because they are lower intensity and that I think brings down the survival for these patients. So that’s important to do. And then move on to maintenance, whether that is post-transplant or in people who didn’t get transplanted and got CPX351, they should really go on to oral azacitidine maintenance. I think that kind of approach of good treatment, transplant, maintenance, like you have to really go through all of these three individual components. And to also remember that if there are targeted mutations, they need to be treated for IDH inhibitors. They have to be on one of these targeted agents, they work really well. And obviously, with therapy-related AML, the ones that do have KMT2A rearrangement, we have the menin inhibitors that are currently ongoing for clinical trials, and they should go on these trials and hopefully we will have an approval in the coming year. So people who have this need to go on the menin inhibitors if this is approved in the future. And that’s important to check at baseline when you know you’re suspecting people with therapy-related myeloid disorders.