Pre-Conference Perspectives on Hematologic Malignancies - Episode 5

Acute Myeloid Leukemia: Novel Targeted Therapies


John Leonard, MD: Now it’s time to move on to AML and Dr. Perl. Again, thank you for being here today.

Alexander Perl, MD: My pleasure.

John Leonard, MD: And I look at AML as a lymphoma doctor but certainly occasionally hearing about AML pain, there seems to be a lot happening. But I also see in some of the studies we’re going to talk about that 7 and 3 hasn’t gone away and people are still working on making it better. So, we’ll get into the details of this. But first, there are a few new agents that it seems like people need to know about. And I keep hearing about the concept of the IDH-1 inhibitor, and how we take that forward. This is a drug, ivosidenib, if I’m saying it correctly?

Alexander Perl, MD: Ivosidenib.

John Leonard, MD: Ivosidenib, thank you. And the net is that it seems like a very important and exciting new agent.

Alexander Perl, MD: And it falls right on the heels of enasidenib, which is the drug from the same company targeting IDH-2. There are 2 different IDH mutations in AML, IDH-1 and IDH-2, that create the same function, but you need different drugs to inhibit the enzyme itself. Enasidenib is the IDH-2 inhibitor and that’s actually FDA approved already. Ivosidenib is targeting IDH-1. And I have to say, if you look at these 2 in separate studies but with very similar patients, they look so similar it’s almost impossible to tell them apart. Enasidenib is a drug that they were able to dose escalate from very low doses to very high doses, from 100 mg all the way up to 1200 mg. They found no obvious dose-limiting toxicities along the way and picked a medium dose to move forward because they had a biomarker to say they were inhibiting the target of the drug and reducing this byproduct of IDH mutation called 2HG, and they did that with very low doses of the drug. They do not see an obvious drug-associated toxicity profile at this dose, but they do see a differentiation syndrome with this drug as they did see with enasidenib. It doesn’t happen in a lot of patients. Here, they saw it only in 11% of patients. But it still does happen, you still do need to look for it. And like APL differentiation syndrome, the patients can get quite sick from this and you need to recognize it and manage it to prevent that complication. But it looks very promising, and I know that this drug is poised to be submitted very soon to the FDA for review based on these data, so this is very exciting.

John Leonard, MD: So, our group has been involved in the studies. I know the Memorial Sloan Kettering Cancer Center Group clearly has also been very involved in this category of drugs. I’ve heard about some pretty impressive responses. I’ve also heard of some that were relatively short-lived. So, it sounds like there’s more work to do. Where do you think this is going?

Alexander Perl, MD: I think one of the exciting and interesting things about AML, and one of the hard things about it, is that it’s a really heterogenous disease. And 1 mutation means you have a target, but it doesn’t mean that if you use the drug, it will always get you the same response. And that’s because these mutations fall in a background of multiple mutations. I think it’s really that combination which opens up the door for, can we target more than 1 mutation with more than 1 drug? And I think that’s the next thing that we’re going to do in the field.

John Leonard, MD: Great. So, the next study is by Wang and colleagues that we wanted to touch on. And this is a study that took older patients with AML, and uses as a backbone, the lower dose ara-C approach that I think people have been using for a while. But now adding in venetoclax, a BCL2 inhibitor, to this approach, the data were fairly interesting. What are your thoughts on this trial?

Alexander Perl, MD: There are actually a few studies of venetoclax added to low intensity chemotherapy. This one looks at low dose ara-C, and last year, there were presentations of venetoclax with hypomethylating agents. The data, again, are very similar. It looks like the addition of venetoclax to that background of low-intensity chemotherapy dramatically increases the response rate. And what’s interesting about this abstract is not really the response rate, which you can do by adding more agents to low-dose ara-C, but the durability of the response is much more important. There have been many drugs added to low-dose ara-C that have had better response rates but no improvement in survival. We can think of clofarabine, we can think of volasertib, we can think of gemtuzumab ozogamicin, and none of those drugs won out in phase III comparisons. This looks very promising because the 1-year survivals actually look very, very good. The median survival on this study is about 11 months. I believe 46% of patients were alive at a year. And those numbers look about twice as good as what you would expect for low-dose ara-C alone.

John Leonard, MD: So, where do you think this is going to fit in relative to the hypomethylating agents, which can also be used in this group of patients?

Alexander Perl, MD: I think the hard thing is many of these patients who get to AML have already seen a hypomethylating agent for their MDS and then develop AML. What’s notable here is a significant proportion of these patients have had prior hypomethylating agents and still responded, which is hard to do with 7 and 3. So, that’s actually quite interesting and some people have even posed the question of, should we be testing regimens like this against a comparator arm with 7 and 3 rather than a comparative arm of low-dose ara-C, which I’m not sure we’re quite ready for but I think that is potentially a question we can move towards.

Transcript Edited for Clarity