Adding Venclexta (venetoclax) to treatment with Vidaza (azacitidine) significantly prolongs survival in people with acute myeloid leukemia (AML) who have not been treated before, a new study demonstrates.

The study, “Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia,” was published in The New England Journal of Medicine. It was supported by by AbbVie and Genentech, which market Venclexta.

Venclexta (marketed as Venclyxto in Europe) is an oral small molecule that is approved by the U.S. Food and Drug Administration (FDA) to treat different types of cancer, including AML in individuals age 75 or older who do not qualify for standard treatment (i.e., chemotherapy). Venclexta works by blocking the activity of B-cell lymphoma-2 (BCL-2), a protein that helps promote cellular survival. By blocking BCL-2, Venclexta primes cancer cells for death.

The new study reports results from the Phase 3 clinical trial VIALE-A (NCT02993523), which evaluated the effectiveness of Venclexta in combination with Vidaza (a chemotherapeutic agent). Some data from the trial have been reported previously; now — having been published — the data has undergone peer review.

VIALE-A enrolled 431 people with AML who were ineligible for standard therapy — because they were 75 or older, had other coexisting conditions that precluded standard treatment, or both — at 134 sites in 27 countries.

The participants were randomly divided into two groups: the Venclexta group (286 participants) was given daily Venclexta (target dose 400 mg) and Vidaza (given by injection on days one through seven of each 28-day cycle, at a dose of 75 mg per square meter of body-surface area). The control group (145 participants) was given the same regimen of Vidaza, but received a placebo instead of Venclexta.

In both groups, the median age was 76 years, and 60% of participants were men.

With a median follow-up time of 20.5 months, the median overall survival time was significantly longer in the Venclexta group than in the control group (14.7 vs. 9.6 months). Statistically, this translates to a significant 34% reduction in the risk of death with Venclexta combined with Vidaza, compared to Vidaza alone.

Significantly more participants in the Venclexta group, compared to the control group, achieved complete remission (36.7% vs. 17.9%), meaning those not showing any signs of cancer. Median duration of this remission was 17.5 months in the Venclexta group and 13.3 months in the control group.

Also, significantly more participants in the Venclexta group achieved complete remission with incomplete hematologic recovery (66.4% vs. 28.3%).
That means the cancer was eradicated, but other blood parameters (e.g., levels of a type of infection-fighting immune cell called neutrophils) were outside normal bounds.

Comparable results were seen across molecular subtypes of AML.

“The combination of azacitidine plus venetoclax … was an effective treatment regimen that led to significant improvements in the incidence of composite complete remission and overall survival,” the researchers wrote.

All participants in the trial reported at least one adverse event, and most (83% in the Venclexta group and 73% in the control group) reported at least one adverse event that was serious in nature. In both groups, roughly a fifth of participants discontinued treatment due to adverse events.

The most commonly reported adverse events (side effects) in the Venclxeta group included: thrombocytopenia (low platelet count, 46%); nausea (44%); constipation (43%); neutropenia (low neutrophil count, 42%); febrile neutropenia (neutropenia with a concurrent fever, 42%); and diarrhea (41%).

The most common serious adverse events in the Venclexta group were febrile neutropenia (30%) and pneumonia (17%).

“The safety profile of azacitidine plus venetoclax was consistent with the known side-effect profiles of both agents, and adverse events were consistent with expectations for an older AML population,” the researchers wrote, adding, “no differences between the two treatment groups with respect to quality-of-life measures were seen.”

“The ability of venetoclax plus azacitidine to improve outcomes of newly-diagnosed AML patients unable to tolerate intensive chemotherapy represents a potentially practice-changing advance in AML treatment,” study co-author Courtney D. DiNardo, MD, of The University of Texas MD Anderson Cancer Center, said in a press release.

Another confirmatory trial called VIALE-C (NCT03069352) is underway. It is evaluating Venclexta in combination with another chemotherapeutic (cytarabine) in people with AML who have not been treated previously.