VIALE-A Trial: Acute Myeloid Leukemia


Dr. Pollyea breaks down data from the recent VIALE-A phase III clinical trial.

Daniel Pollyea, MD, MS: The VIALE-A trial was a landmark confirmatory study mandated by the FDA for full approval of venetoclax. It was a randomized study that enrolled newly diagnosed patients with AML [acute myeloid leukemia] who were older or unfit for intensive chemotherapy. It randomly assigned them to receive azacitidine alone, which has been the standard of care in the United States for this population, or venetoclax plus azacitidine. The results were very clear. Based on all the relevant end points, including response rate and survival, the venetoclax arm was really superior. There were much higher response rates and a significant improvement in overall survival. As a result, this has become the standard of care for this population of patients with AML.

There are some really intriguing data around the ability to achieve MRD [minimal residual disease] negativity with a venetoclax-based regimen. This is a less intensive therapy, so it was unclear whether this would allow for a deep response, an MRD-negative response. We had some data from Keith Pratz at the recent ASCO [American Society of Clinical Oncology Annual Meeting] showing that a significant percentage of patients can achieve MRD negativity with a pretty stringent MRD assay, and they appear to have more durable responses and improved overall survival.

First, it’s very exciting to see that a low-intensity regimen can allow these deep types of responses. This goes back to the mechanism that I mentioned before that this can target the leukemia stem cell population. Maybe it’s not surprising that this can allow for these deep types of responses, but it also shows that these are better responses clinically. The next step is going to be figuring out who these patients are that are having deep responses and how that can be replicated in other patients who aren’t responding as well.

It’s very important to look for all the different mutations in patients, as we discussed before. Several have approved targeted therapies. I’m talking about FLT3 and IDH, both of which are mostly in the relapsed/refractory setting. But there’s some interest in whether this information in the up-front setting might be helpful and if this should be the preference to target a targetable mutation in the newly diagnosed setting, or to use a venetoclax-based regimen.

It’s my opinion, and the opinion of most of my colleagues, that while that could be a future strategy to target a genomic mutation in the up-front setting, most of us would prefer to continue using a venetoclax-based regimen for a couple of reasons. One is that there do not appear to be worse outcomes with respect to response rates with patients with FLT3 or IDH mutations with venetoclax-based regimens. To the contrary, patients with IDH mutations have unusually good responses to venetoclax-based regimens. The second issue is more of a logistics issue. Starting a venetoclax-based regimen for any patient with any gene mutation allows you to get started with a treatment more quickly than if you had to wait for the results of a gene mutation, like FLT3 or IDH. This is also reflected in the NCCN [National Comprehensive Cancer Network] Guidelines that the standard of care, even with patients with known FLT3 or IDH mutations, is still to give venetoclax-based regimens. We’ll see if this changes in the future. There are some emerging data that IDH inhibitors plus azacitidine might also be very effective. We’ll see how that holds up in the near future.

Transcript edited for clarity.

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