Transcript

My name is Courtney DiNardo, and I am from MD Anderson in Houston, Texas. I wanted to talk a little bit about the results of the VIALE-A study, which is the randomized, placebo-controlled study of azacitidine with or without venetoclax for newly diagnosed, older patients with acute myeloid leukemia.

Just as a bit of background, the majority of patients with acute myeloid leukemia are older in age, about 68 to 72 years on average. The majority of our older patients have challenges with comorbidities and higher-risk genomic features, just making them at really high risk and oftentimes inappropriate for standard intensive chemotherapy.

For these patients, we're often giving azacitidine, low-dose cytarabine, decitabine, as the standard lower-intensity treatment option, which is definitely an appropriate thing to do.

Our patients do benefit from those approaches, but unfortunately, only the minority will respond. The median overall survival when you use one of these approaches is unfortunately under a year.

The point of the VIALE-A study was to see in a randomized, confirmatory, phase 3 study whether the combination of azacitidine with the oral BCL-2 inhibitor venetoclax really improves the outcomes, in terms of both responses as well as an improvement in overall survival.

There was a phase 1 study that actually led to an accelerated FDA approval within the United States. This is that confirmatory phase 3 study, trying to confirm once and for all that the combination really is providing that clinically significant improvement.

Just going through the study in detail, a little bit of detail, at least, there were over 400 patients that were enrolled throughout the world. It was an international study. It was randomized and placebo-controlled, 2:1 randomized to the combination of aza and ven versus azacitidine alone. The primary end point was overall survival.

In terms of the responses that were seen, looking at a composite remission rate, which is the CR and the CR with incomplete count recovery, or so CR and CRi, with azacitidine alone, it was about 28%, which is exactly what you would expect to see with azacitidine alone.

That's consistent with our historical expectations. Compare that to the combination with aza and ven, where the composite remission rate was 66%, so more than doubling the remission rate. Also, really important is that remissions happen relatively quickly.

The average time to a first CR or CRi was 1.3 months. Many patients within that first cycle are going into a remission. Remissions really happened across the board, looking at different higher-risk genomic features, like secondary AML or complex cytogenetics.

Both younger and older patients, the cutoff at 75 was used, all those patients benefited, improvement in response rates really across the board, which was really great to see, of course. Then the primary end point was overall survival.

With azacitidine alone, the median overall survival, 9.6 months, which, again, is very consistent with what we would expect azacitidine to do in this population. With the combination, improvement up to 14.7 months, so close to 15 months overall survival on average.

Which really is, I think, definitely a step forward, as there really hadn't been studies to-date that have been able to move that needle, get our patients living beyond just a year in this high-risk population.

I think it's a really clinically meaningful achievement, as well as the fact that many of those patients who go into remission have a durable remission, extending well beyond a year. Many of those patients are still on and doing well in an ongoing remission at the time of the last cut for this data analysis.

In terms of safety, I do want to mention 1 or 2 things. The first is that tumor lysis syndrome is definitely something to be aware of when you're using venetoclax. Only 3 patients on the combination experienced tumor lysis syndrome.

All 3 of them happened during the first week when the patients were having that venetoclax dose ramp-up, and in all cases, it was very easily managed. Dosing was not needed to be held, just with electrolyte replacements and the like.

That's with mitigation techniques taken into consideration. You needed a white count under 25,000 to start. You can use hydrea for that to happen. You needed to be on a uric acid-reducing agent prior to starting.

IV fluid for rehydration, daily chemistries during that dose ramp-up to make sure that no tumor lysis was developing. Just important to make sure that that is followed so that tumor lysis doesn't happen when using this therapy in the community.

The other thing to be aware of is cytopenias and cytopenia-related infections, which are more common on the combination. I think the most important thing here is just to make sure that you're monitoring counts, of course.

Also, making sure that you're doing that end of cycle 1 bone marrow, because that's a really critically important piece of information. Many of our patients are going into remission within that first month.

You want to do that bone marrow at the end of the cycle. If there is no residual leukemia, but the counts are still low, then you hold on the next cycle. You wait a week or 2 and allow for counts to recover before you start the next cycle.

That's a really important thing to do so you're not compounding more therapy on top of an already myelosuppressed marrow. The majority of patients—actually, more than 50% of patients on the combination—required an interruption between cycle 1 and cycle 2.

It's not a failure in any way. It's just something you need to be aware of and hold before you start the next cycle. With those 2 key treatment algorithms, I think the audience is ready.

Just, again, in conclusion, the combination, I think, shows that the use of azacitidine with venetoclax really improved not only responses but overall survival and several other key secondary end points, and it should be considered a new standard of care for our older AML patients. Thank you.