Biomarkers Accumulate in the Acute Myeloid Leukemia Paradigm

Moving beyond the prior treatment standards in acute myeloid leukemia (AML) consisting of chemotherapy and hypomethylating agents, there are now a number of new advances for patients.

According to Eytan M. Stein, MD, a hematologic oncologist from Memorial Sloan Kettering Cancer Center, since 2017 alone, a variety of new drugs have been designed to care for patients with AML, specifically in regard to FLT3 inhibitors.

For patients with a FLT3 mutation, a FLT3 inhibitor can be added to a 7 plus 3 regimen of cytarabine and daunorubicin. Some patients also can get the combination of hypomethylating agents with venetoclax (Venclexta), a BCL-2 inhibitor.

The use of allogeneic stem cell transplants (ASCT) has also been further understood over the years and its benefit shown more clearly. Experts have determined how to find a donor for every patient, whether that be through using a sibling, parent, or a child as their stem cell donor. Treatments against graft versus host disease (GVHD) have also improved, reducing a major toxicity of ASCT.

Further, a new class of drug, menin inhibitors, are currently in development and aim to treat acute leukemia. The focus is on treating patients with rearrangement of the MLL gene, and those with acute leukemia that have an NPM1 mutation. Stein adds that these menin inhibitors seem promising in reversing MLL rearranged leukemia and getting patients to remission.

In an interview with Targeted Oncology^TM, Stein discusses the latest treatment developments and updates within the AML space.

What does the current landscape of acute myeloid leukemia consist of?

We break down our treatment regimens into intensive induction chemotherapy, so strong chemotherapy given in the hospital, and then we also break it down into lower intensity therapies that can be given outside of the hospital. The intensive induction chemotherapy are drugs like 7 plus 3 cytarabine and daunorubicin.

If you have a FLT3 mutation, we add on a FLT3 inhibitor to the 7 plus 3. Some patients have certain kinds of leukemia where they benefit from a liposomal formulation of 7 plus 3, and that's sort of that large group of patients. Then the other group is these older patients with acute myeloid leukemia who really wouldn't do very well if you gave them 7 plus 3 based therapy. Those patients typically now will get the combination of a class of drugs called hypomethylating agents with a BCL-2 inhibitor called venetoclax. That's very exciting because it leads to remission rates in about 70% of patients.

Before we had this regimen, the remission rate in that patient population was closer to 20%. For some patients, they can have a durable response. When it comes to relapsed and refractory acute myeloid leukemia, we're still talking about single agent small molecule inhibitors of FLT3, IDH1, and IDH2 mutations. Those drugs are given a single agent for relapsed and refractory disease.

How does the landscape differ from what it was a decade ago?

I started as a fellow in hematology medical oncology in 2010 when there were 2 treatments for acute myeloid leukemia. There was chemotherapy, and there was a class of drugs called hypomethylating agents. What you did was pretty simple because there weren't that many choices to make. If a patient came with AML, you got 1 or 2 choices on what to give them.

Since 2017, there's been an explosion of new drugs for patients with acute myeloid leukemia. There is a huge explosion in research into other pathways and things we can target to help improve the outcomes of patients with acute myeloid leukemia as well. I also want to highlight that part of treatment for acute myeloid leukemia is allogeneic stem cell transplants. The benefit of allogeneic stem cell transplants has greatly increased over the past 1 to 2 decades, for 3 reasons.

One reason is because we've figured out how to find a donor for every patient. There used to be a large group of patients who didn't have a donor, but now we do what's called haploidentical stem cell transplants, where patients can use a sibling, parent, or a child as their stem cell donor. That's one big advance. We have better treatments against graft versus host disease, which is a major toxicity of allogeneic stem cell transplant. We're also able to transplant patients who are much older now at Memorial Sloan Kettering and maybe down in Florida.

At Baptist, we tell patients that there is no upper age limit to an allogeneic stem cell transplant, you get a transplant if your organs work well and if you can sort of get around on your own you can get a transplant. Our places started transplanting 78, 79, even 80-year-old patients sometimes if they are otherwise in good health. Those are big advances and I'm very excited to see that because I think that's helping drive the improvement in overall survival that we've been seeing from these drugs that are helping people get into remission.

TARGETED ONCOLOGY: In terms of using targeted therapies in AML, what are the main questions oncologists have.

Our focus has been understanding targeted therapies for acute myeloid leukemia, but specifically understanding how we overcome resistance that develops to targeted therapies when patients are being treated with them for AML. In order to understand how you overcome resistance, you have to understand the causes of resistance. I spent a fair amount of time talking about drugs that are given as single agents for patients with relapsed and refractory AML, like IDH inhibitors and FLT3 inhibitors.

I then went through a lot of data about what mediates resistance to those drugs during a recent conference presentation. That is if a patient goes into remission, but then relapses and almost everyone relapses on these drugs, what's driving that relapse? Finally, I propose a mechanism by which we can help avoid the relapses that occur with single agent inhibitors.

I may have painted a rosy picture talking about the available therapies, but really the picture is not that rosy. People are doing much better than they did before but even though the overall survival has improved for many, the majority of those patients are going to end up relapsing. We went from a place where we really didn't have any treatments that worked very well, to a place where now patients have a median overall survival of maybe a year and a half if they're older than 70, or 75.

As an academic oncologist, that's amazing, but in real life, that's not so amazing. If I told you, you had a year and a half to live, you'd be pretty upset, and I'd be pretty upset. There are major areas where we still need to improve on this initial success that we've had. There's some particularly poor risk groups of patients, specifically patients with what are called a complex karyotype and p53 mutations, but those patients really don't do very well with anything. We really need to understand the science better to understand how we can improve the outcomes for those patients as well.

What novel therapies are coming down the pipeline in AML?

There's a new class of inhibitors called menin inhibitors. When it comes to the development of acute leukemia, a specific subtype of acute leukemia that is a rearrangement of the MLL gene, and an acute leukemia that has an NPM1 mutation. What's interesting about these kinds of leukemias, specifically MLL rearranged is they occur both in adults and kids. You don't see that much but we see it in this disease. There are these drugs called these menin inhibitors that are very good at reversing MLL rearranged leukemia and putting these kids and adults into remission.

What advice do you have for community oncologists treating this patient population?

One thing that's important is attending CME activities, because it has become very complicated to treat acute myeloid leukemia. Some community oncologists see a lot of acute myeloid leukemia, and some doctors don't see as much.If you don't see as much and you're not completely comfortable with it, you should work with someone at an academic medical center to get opinions.

It would be like me trying to treat lung cancer, I have no idea how to treat lung cancer and I'd have to go to the community oncologist to ask them because they probably treat a million more of those than I do. I think it's okay to ask for help and to ask questions, and to attend CME activities. CME activities are extremely important in keeping up to date with what's going on, especially with all the changes that are happening.