Venetoclax/Azacitidine Slated as New Standard in Older Patients With AML Ineligible for Intensive Therapy

Courtney D. DiNardo, MD, MSCE

The combination of azacitidine plus venetoclax led to statistically significant improvements in response rates and overall survival (OS) in elderly patients with acute myeloid leukemia (AML) ineligible for intensive therapy, according to Courtney D. DiNardo, MD, MSCE.

In a multicenter, randomized, double-blind phase 3 study (NCT02993523), investigators evaluated the efficacy of the combination of azacitidineplus venetoclax as compared with azacitidine plus placebo in older patients with AML who were not candidates for intensive therapy.

As of January 4, 2020, a total of 431 patients were randomized to receive the combination (n = 286) or azacitidine plus placebo (n = 145). Results showed that, with a median follow-up time of 20.5 months, the median overall survival (OS) was 14.7 months in the combination arm and 9.6 months in the control arm, which translated to a 34% reduction in risk of death (HR, 0.66; 95% CI, 0.52-0.85; P <.0001).

Composite complete remission (CR)/complete remission with incomplete count recovery (CRi) rates in the combination and control arms were 66% and 28%, respectively (P <.001). The median time to the first CR/CRi response was 1.3 months and 2.8 months, respectively. The duration of CR/CRi was 17.5 months with the combination versus 13.4 months with azacitidine alone.

“The combination of azacitidine and venetoclax should be considered a new standard of care for our older patients who are not getting standard intensive chemotherapy,” said lead study author DiNardo. “Not only were there significant improvements in OS, but the response rates were doubled, and the duration of remission was improved. All the secondary key end points were also significant. This represents an excellent new treatment for our patients.”

In an interview with OncLive, DiNardo, who is also a clinical researcher in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the results of the study evaluating the combination of azacitidine plus venetoclax in elderly patients with AML.

OncLive: Could you shed light on the current unmet need for patients who are ineligible for intensive therapy?

DiNardo: The majority of our patients with AML are older; the average age [of these patients] is 68 to 72 years at the time of diagnosis. Since our patients are older, due to both medical comorbidities and higher risk of disease related biology, the prognosis has been poor for decades. Our patients don't tolerate intensive chemotherapy well. Lower-intensity strategies, such as azacitidine, decitabine, or low-dose cytarabine are effective, but they are associated with remission rates of 30%-40% and a median survival that is less than 1 year.

Although we do have therapies to offer, they are suboptimal. In a phase 1 study, the addition of the oral BCL-2 inhibitor venetoclax to either azacitidine or decitabine provided impressive remission rates in addition to signals of durable responses. As such, in the larger phase 3 confirmatory trial, we hoped to see that the combination of azacitidine plus venetoclax provided benefit.

What was the design of this trial?

This was a large, international, double-blind, placebo-controlled, phase 3 study and a total of 433 patients were randomized. Patients were eligible if they were an adult with newly diagnosed AML, who had 1 of a host of comorbidities making them ineligible for intensive chemotherapy. This was a 2:1 randomization where patients received azacitidine with venetoclax or azacitidine with placebo.

The primary end point of the trial was OS. We were looking to see whether this combination provided clinical benefit in terms of improving the average OS in patients. The secondary end points of this trial were remission, composite remission rates, time to first remission, transfusion independence, event-free survival, and the evaluation of responses in different molecular subgroups.

What was seen in terms of efficacy with the combination?

The patients who were on the placebo arm received azacitidine alone and the remission rate was [under] 20% and the CR/CRi was approximately 30%; this is what we expected to see. With the addition of venetoclax, we saw a CR rate of about 36% and a CR/CRi rate of about 66%. [The addition of the agent] more than doubled the remission rate; that was clinically meaningful and statistically significant. This held true across all evaluated subsets, including patients with high-risk cytogenetics, FLT3 mutations, NPM1 alterations, IDH1/2 mutations, and the other different mutations assessed.

Again, the primary end point of the trial was OS. There was a median follow-up time of almost 2 years for this study; it has been going on for quite some time. We saw an improvement in OS, which was very exciting to see. This was one of the first phase 3 study that analyzed older, newly diagnosed patients and showed a demonstrable survival benefit. A median OS of approximately 10 months [was observed] with azacitidine alone versus 14.7 months with the combination.

Did the combination have an acceptable safety profile? What were some of the most common adverse events that were reported?

The safety profile of the combination was expected. In the phase 1 study, we saw that it was well tolerated; for example, no increase in 30- or 60-day mortality was observed. We did see an increase in cytopenias, especially neutropenia and neutropenia-related infections. This is something to be aware of. To this end, we monitor patients on this combination closely with labs and ensure that we do a bone marrow at the end of cycle 1. This is not something that we always do when patients are receiving azacitidine alone. In those cases, we tend to do bone marrows about 3, 4 or later. But getting that end-of-cycle-1 bone marrow is really important because many of our patients will be in remission at the end of the first cycle.

If their counts are low around day 28, it's not because they still have disease; their disease is actually gone. We just need to wait another week or 2 for their counts to recover from the combination therapy. There are some important management guidelines in terms of monitoring cytopenias and giving the combination based on count recovery.

Reference

1. DiNardo C, Jonas B, Pullarkat V, et al. A randomized, double-blind, placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naïve patients with acute myeloid leukemia ineligible for intensive therapy-VIALE-A. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract LB2601. bit.ly/3gf4FtA.