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Older patients with acute myeloid leukemia (AML) had clinically meaningful improvement in overall survival (OS) when they received the Bcl-2 inhibitor venetoclax (Venclexta) in addition to standard therapy, a randomized trial showed.

Median OS increased from 9.6 months with azacitidine plus placebo to 14.7 months with the addition of venetoclax. More than twice as many patients achieved complete response (CR) with venetoclax, and substantially more patients attained transfusion independence with the combination therapy.

Febrile neutropenia and dose interruption occurred more often in venetoclax-treated patients, but a similar proportion of patients in both groups discontinued treatment because of adverse events, during the .

"We're delighted to confirm that the combination of azacitidine and venetoclax for newly diagnosed older AML patients ineligible for standard intensive chemotherapy led to a significant improvement in overall survival," said Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center in Houston. "Responses occurred rapidly, often within one cycle, and were seen across all cytogenetic risk groups and molecular mutations. The safety profile includes increased cytopenias, in particular neutropenia, which can be effectively managed with appropriate neutropenia management guidelines."

"The combination of azacitidine and venetoclax was associated with statistically significant and clinically meaningful improvement in overall survival, response rates, duration of remission, and transfusion independence and represents a true paradigm shift in the treatment of older patients with AML," DiNardo said.

Session moderator Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland, said the presentation provided evidence of efficacy in a patient population "in dire need of new medications."

AML primarily affects older adults, as various studies have shown a median age of about 70. Patients 75 or older or who have significant comorbidities frequently are ineligible for intensive induction chemotherapy, which is associated with .

Standard treatment with low-dose hypomethylating agents (HMAs) also yields inferior outcomes: low response rates, prolonged time to response, and median OS less than 1 year, DiNardo said.

Bcl-2 is overexpressed in AML and in AML stem cells. Venetoclax, which is highly specific for Bcl-2, demonstrated in combination with HMAs in a phase Ib clinical trial involving untreated older patients with AML. The findings provided a basis for evaluating azacitidine plus placebo or venetoclax as initial treatment for patients with AML. Several countries have already approved the combination of venetoclax and azacitidine as first-line treatment for older patients with AML, DiNardo noted.

The randomized trial involved patients with newly diagnosed AML ineligible for intensive therapy. Investigators at 180 hospitals located around the world randomized 431 patients 2:1 to receive venetoclax or placebo, both in combination with azacitidine. OS was the primary endpoint; secondary endpoints included CR (as defined several ways), transfusion independence, and event-free survival (EFS).

Median patient age was 76, and about 60% of the patients were 75 or older. Three-fourths of the patients had de novo AML, two-thirds had AML without myelodysplastic changes, 45% had ECOG performance status 2-3, about half had bone marrow blast count of 50% or greater, and two-thirds of the patients had intermediate-risk cytogenetics.

After median follow-up of about 20 months, patients in the venetoclax arm had a 34% reduction in mortality risk versus the placebo group (HR 0.66, 95% CI 0.52-0.85, P<0.001). Median treatment duration was 7.6 months with venetoclax and 4.3 months with azacitidine plus placebo. Results favored venetoclax regardless of sex, patient age, de novo vs secondary AML, cytogenetic risk (intermediate vs poor) or molecular markers associated with the disease.

The CR rate (including CRi, incomplete blood count recovery) was 66.4% with venetoclax versus 28.3% with placebo (P<0.001). DiNardo said 43.4% of patients in the venetoclax arm attained CR/CRi status during the first cycle of therapy, as compared with 7.6% of patients allocated to azacitidine and placebo. A subgroup analysis showed a consistent, large difference in CR favoring venetoclax.

The median duration of CR/CRi was 17.5 months with venetoclax and 13.4 months with placebo. A separate analysis limited to patients who achieved CR yielded a similar difference in response duration.

Significantly more patients (P<0.001) in the venetoclax arm achieved transfusion independence for at least 8 weeks. The advantage for the combination arm was evident whether the transfusion-free interval was defined by red blood cell count (60% vs 35%), platelet count (69% vs 50%), or both (58% vs 34%).

Grade 3/4 hematologic adverse events (AEs) occurred in 82% of the venetoclax arm versus 68% of the placebo group. Thrombocytopenia (45% vs 38%), neutropenia (42% vs 29%), febrile neutropenia (42% vs 19%), anemia (26% vs 20%), and leukopenia (21% vs 12%) all occurred more often with venetoclax. Grade 3/4 nonhematologic toxicity was more common with azacitidine and placebo (31% vs 17%), with hypokalemia being most frequent in both arms (10%-11%).

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