DR STONE: Venetoclax is a Bcl-2 inhibitor. So Bcl-2 is an antiapoptotic protein that prevents cells from dying in response to chemotherapy and other genotoxic stress. And we have 2 super investigators. One happens to be at MD Anderson, Marina Konopleva, another one at my place, Tony Letai, who’s done a lot of work with showing how you can predict who’s going to respond to Bcl-2 inhibitors and, more specifically, combining Bcl-2 inhibitors with chemotherapy.

So you stress the cell and you enable it to die by giving the Bcl-2 inhibitor. And, as we all know, it was so powerful in CLL it caused tumor lysis syndrome. And that delayed its approval for a while, because it was dangerous. It’s not causing tumor lysis syndrome in AML. We, MD Anderson and Dana-Farber, have a paper coming out.

As a single agent, venetoclax has about a 20% CR rate in AML, relapsed/refractory. And then, in older adults with AML, we’ve combined it with hypomethylating agents, “we” meaning a lot of different hospitals, but D-FCI and MD Anderson among them. The preliminary results of that trial were presented at ASH. You can see the slide here.

If you look at this slide, which shows the response rate — now, these were older adults who were being treated with hypomethylating agents, where the complete remission rate is about 25% and the overall response rate is about 50%. We’re getting response rates in the neighborhood of 80% or even higher combining hypomethylating agents with venetoclax. So we need to work out the dose. It’s a little marrow toxic. But I’m very excited about this.

I have an 81-year-old African-American lady that I put on this trial. And she’s been in remission for months. We’ve had to cut back the dose. But that’s an anecdote, obviously, but it exemplifies what might be the possibility with this drug. We’ll need a randomized Phase III trial, I think, aza plus or minus ABT-199, to show that. ABT-199 is the developmental name for venetoclax. But I’m optimistic that this’ll be important in a lot of types of cancers, actually.

DR LOVE: So Jorge, I was just flashing, we did a very similar program here — actually, your colleague, Dr Garcia-Manero was on the faculty — looking at MDS. It just got published, actually. And he was talking about ABT-199, venetoclax, and a hypomethylating agent, in MDS. Can you just reflect in general, what’s going on at MD Anderson in terms of looking at this agent?

DR CORTES: Yes. I mean, it’s a fascinating drug. And, as Rich mentioned, the idea with venetoclax is to keep apoptosis alive, which is kind of a twist on the word, on what apoptosis means. But that’s essentially what you’re trying to do. And Bcl and its family of proteins, antiapoptotic and proapoptotic proteins, are very relevant in many diseases. We talked about CLL, MDS, AML, even in MPNs in CML, et cetera.

So we have a very wide panel of trials, certainly in CLL. But in AML, we’re doing all these hypomethylating combinations. The data, the preliminary data, is very attractive. So we are looking at these combinations and trying to identify the subset of populations. As it turns out, for example, it looks like IDH-mutated patients are particularly prone for a good response to venetoclax for some reason.

And we are also starting to combine it with some of these other targeted therapies, where we’re going to be looking at the combination with the IDH inhibitors for that same reason. So I think that starting to explore these combinations with different hypomethylating agents and other targeted therapies, I think, would be very useful. And we do have a number of trials like these at MD Anderson.

Module 1: Current and future approaches to targeted therapy for acute myeloid leukemia (AML)

Module 2: Other clinical issues in AML management

Module 3: Case discussions