VIALE Studies in AML

Harry Paul Erba, MD, PhD: Let’s move on to newly diagnosed AML [acute myeloid leukemia] patients who are unfit for chemotherapy. I’m going to have Dan start with this. Dan, you’ve been a leader from the beginning in the phase 1B studies with hypomethylating agents [HMAs] with venetoclax. Why don’t you tell us about the practice-changing abstracts that have been presented at EHA Congress and ASH [American Society of Hematology Annual Meeting] regarding those venetoclax combinations.

Daniel Pollyea, MD, MS: Thanks, Harry. Most of us who treat AML have been very excited these past couple of years to see what venetoclax can do for some of these patients. As you said, the patients we’re focusing on here are older patients, who either by reason of age or comorbidities are not fit for standard intensive induction chemotherapy at the outset. They’re receiving either venetoclax in combination with either a hypomethylating agent or low-dose cytarabine.

With respect to the hypomethylating agent, we’ve had approval for the last year and a half based on some phase 2 data, a noncomparative study showing very promising response rates and survival. We all were anxiously awaiting Courtney DiNardo’s presentation at EHA [European Hematology Association], which was going to finally show us in a randomized setting how venetoclax plus azacitidine did in this population versus azacitidine alone. Most of us who have worked in AML know this is a critical test, a time when a lot of prior therapies have not been able to surmount this challenge in a randomized setting.

Most of us who treat this disease were relieved and very happy to see the data for the venetoclax arm really performed very consistently with what we have come to expect, based on the phase 2 data. We were not disappointed, at least specifically looking at the venetoclax patient—you know, a response rate somewhere north of 60%, 65% and a survival on the order of 15 months. The critical thing was to compare it with the azacitidine arm, and we’re ready for some twist or something thrown at us, in the underperforming or overperforming arm. In fact, the patients who received azacitidine performed pretty much how we would have expected them to historically. We saw a nice statistically and clinically significant improvement with respect to response and survival.

Those of us who have been using this frequently in the last year and a half, based on the approval, are reassured that this likely the new standard of care in this setting.

Just to comment quickly, because it was raised: There’s also the question of combining this with low-dose cytarabine, which is a much more commonly used drug in many other places in the country. Similar enthusiastic data around the phase 2. We had, based on a press release and some other information, the impression that the study would not be positive when compared with low-dose cytarabine alone. Gail is, I believe, the senior author of that study that was just published in Blood. I encourage people to read it, because when patients were followed for a little longer than the original planned analysis, which is definitely a weakness of the planning of the study. But the reality of it was that when you follow patients to a 12-month time point, there was a survival benefit.

There are a lot of explanations for why the low-dose cytarabine patients seemed to underperform. It is, by definition, a tougher patient population. Upward of one-third of those patients were allowed based on who had had a prior hypomethylating agent for an MDS [myelodysplastic syndrome]. Those patients were completely excluded from the azacitidine arm. There are a couple of explanations there. But it gives us more options. For us in the leukemia world, there’s no way that’s not a good thing.

Harry Paul Erba, MD, PhD: Gail, did you want to chime in?

Gail J. Roboz, MD: The VIALE-A study, as it’s now kind of widely known as, looks at azacitidine plus venetoclax versus azacitidine alone. That’s the new standard of care for AML. It’s actually really rough in Europe, where they don’t have it yet, and in other parts of the world where they don’t have it yet, because we’ve seen incredibly higher-than-usual response rates. We’ve been stuck in 28%-to-30% response land for older patients with AML for decades. Now that’s not true. Those over-60% response rates across cytogenetic groups, across molecular groups are real. They happen. They’re quick. You don’t have to wait for 100 cycles of azacitidine to see those responses. It’s usually 1, sometimes 2, but usually after 1. It’s just plain better. I think Dan is absolutely right that we were relieved. First of all, there were a couple of other studies presented at ASH in which the azacitidine arm was looking a lot better than we thought. There were patients hanging out for a year or 11 months of overall survival. This, of course, was a survival study. So that was a little worrisome.

Then you have the VIALE-C trial, the low-dose Ara-C [cytarabine] study, and actually I am a senior author on that paper. Andrew Wei is first. We’re putting together an editorial to explain that. Clinically, it’s a useful regimen. Those response rates were real. It is absolutely overshadowed by the azacitidine data, but sometimes we really do have patients who had 10 cycles of the hypomethylating agents before they officially convert to AML, or who are in a situation where you just don’t think that another round of HMA is going to work.

The question is, can some of those patients still benefit from the addition of venetoclax to low-dose cytarabine? I still think there are patients for whom there might be a benefit. Much like the phase 3 data we saw years ago regarding decitabine, which initially did not show a survival benefit but then with longer follow-up did, I think those studies are statistically kind of messed up. The reason you’re not seeing the benefit is more because of disadvantageous study design with respect to hazard ratio and statistics, rather than because the regimen doesn’t have any benefit.

AZA-VEN [azacitidine-venetoclax] is the new standard of care. There are probably some patients for whom I would try low-dose Ara-C [cytarabine]–venetoclax if you really don’t think more HMA is going to be of benefit. The rest of the world is scrambling to try to get the regulatory approvals so that they can apply these—the practice-changing regimen for their patients.

Transcript Edited for Clarity