Venetoclax in AML

Transcript:Elias Jabbour, MD: Richard, we hear a lot about the new drugs, and one of the most exciting drugs to wait for to get an approval, hopefully, is venetoclax. There was good data printed last year by my colleague, Dr. DiNardo, and other investigators, about combining this drug with cytarabine/Vidaza. At this ASH meeting, we have the combination with low-dose Ara-C. What’s your impression of the drug?

Richard M. Stone, MD: Well, I think this represents a whole new area of therapeutic development, and it really dates back to the late 90s when Korsmeyer described how cells die in response to DNA damage. And we’ve got agents, like venetoclax, which inhibit BCL2, freeing up things that can damage them, that allow cell death through a cytochrome C release through the mitochondria. And there are other agents, like MDM2 inhibitors, which activate p53 and allow cell death through that mechanism, and maybe even MCL1 inhibitors that are another limb of the cell death pathway. So, this is a protean global issue in cancer. And venetoclax is already approved in 17p deletion CLL, which is a very malignant disease, primarily because p53 is dysfunctional in those patients.

So, there is excitement about using venetoclax in AML and MDS, in our field based on a single-agent trial, which we published this year in Cancer Discovery, looking at venetoclax as a single-agent. Response rates weren’t outstanding—19% CR rate—but it was active. And when you combine it with an agent that is already pushing the cells toward dying, like azacitidine and decitabine, you might be able to get even more bang for your buck. And so, AbbVie launched one trial in which venetoclax was combined with either azacitadine or decitabine at various doses. You’re right: the dose escalation part of that trial was presented last year at ASH, and it showed a combined response rate with venetoclax in one of the HMAs (hypomethylating agents) in the 70% range.

Elias Jabbour, MD: Negativity as well, which is after 1 or 2 courses.

Richard M. Stone, MD: In some cases, yes, that hasn’t been fully vetted.

Martin S. Tallman, MD: Untreated patients, if I’m correct.

Richard M. Stone, MD: Yes, untreated patients. And at this meeting—just to finish on this venetoclax issue—there was a very important abstract presented by Andrew Wei from Australia, who also presented results of an AbbVie-sponsored trial in which untreated AML patients—and some patients who failed HMA when they had MDS—got low-dose Ara-C with venetoclax. And the response rate was similarly very high, much higher than expected from low-dose Ara-C alone. Very early data suggest the 1-year survival is impressive.

Elias Jabbour, MD: Well, just 1 more question about the venetoclax. Physicians in the community in the USA are using the drug off-label. As you mentioned, it is approved for 17p deletion CLL patients who failed other therapies. Do you have any concern about tumor lysis syndrome or dose escalation at the beginning?

Richard M. Stone, MD: The good or bad news, depending on how you look at it in AML, is there has been no tumor lysis syndrome in any of the trials I mentioned. It’s effective, but not as effective as it is in CLL unfortunately, or fortunately. So, we don’t have to worry about that particular thing, although we’re still being very cautious just in case.

Elias Jabbour, MD: Excellent. So, I want to wrap up with the new drugs. There are other new drugs available. We have the checkpoint inhibitors, we have guadecitabine, and others. I want to start with you, Mark. What’s your impression of the new drugs? Which one is the most promising? And, how do you follow them?

Mark J. Levis, MD, PhD: Actually, venetoclax, to me, was quite exciting. It reminds me of rituximab—it seems to work whenever you combine it. But, I think there’s actually stacking up; coming down the pipeline, there’s going to be some very interesting drugs. There’s the resurrection of Mylotarg in the form of this cytogenetic, anti-CD33 drug-antibody conjugate. Again, the data look similar to the hypomethylating agents combined with venetoclax, where you go from a 20% response rate up to a 70% response rate. And your colleague, Dr. Fadi Braiteh, will be presenting those data at this meeting. I think that’s a particularly exciting time. We can take such an agent and study it in the core-binding factor leukemias, in leukemias where Mylotarg seemed to have been successful. Guadecitabine is a fascinating drug. We’re going to make new, improved decitabine. We’re going to take a CpG island, essentially in the form of a drug, and see if we can get that as a more effective hypomethylating agent. So, there are several phase III studies of that going on right now.

Yes, there are lots of FLT3 inhibitors all stacking up. That’s a very crowded field. We’re all delighted that, in fact, we’ve made the first major leap in that with the RATIFY trial, but quite literally stacked up are gilteritinib, quizartinib, and crenolanib breathing down their necks. Sorafenib is not being developed specifically for AML, but it’s on the street, if you will, and it’s perhaps the most heavily used FLT3 inhibitor right now. So, I think those are the drugs that are going to be closest to approval. For the other exciting agents, I think it’s still a little bit too early to judge whether or not anything is coming.

Transcript Edited for Clarity