Venetoclax regimen extends OS in AML subset
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The addition of venetoclax to azacitidine extended OS among treatment-naive patients with acute myeloid leukemia ineligible for intensive therapy, according to study results presented at Society of Hematologic Oncology Annual Meeting.
The regimen also exhibited a manageable safety profile among the predominantly elderly cohort, according to the results, which were previously presented at this year’s virtual European Hematology Association (EHA) Annual Congress.
“Current therapy options for AML include standard induction therapy, which is typically intensive chemotherapy,” Courtney D. DiNardo, MD, MSCE, associate professor in the department of leukemia of the division of cancer medicine at The University of Texas MD Anderson Cancer Center, told Healio at the time of the EHA presentation. “However, not all patients are able to tolerate the standard intensive chemotherapy, often because of age, abnormal organ function or comorbidities. There is such a need for effective therapies for patients who cannot withstand chemotherapy. Even with current therapies, the 5-year survival rate for patients with AML remains at approximately 29%.”
Venetoclax (Venclexta; AbbVie, Genentech) — an oral BCL-2 protein inhibitor — is approved in the United States for use in combination with azacitidine, decitabine or cytarabine as front-line treatment for older patients with AML who are unfit for induction chemotherapy.
DiNardo and colleagues conducted the randomized phase 3 VIALE-A trial to evaluate the efficacy of venetoclax plus azacitidine for treatment-naive patients with AML ineligible for intensive therapy.
The double-blind, multicenter trial included 431 patients (median age, 76 years; range, 49-91) with AML who were ineligible for intensive induction therapy due to age or comorbidities.
Researchers randomly assigned 286 patients to azacitidine dosed at 75 mg/m2 on days 1-7 of each 28-day cycle plus oral venetoclax dosed at 400 mg daily. The other 145 patients received azacitidine plus placebo.
The venetoclax and placebo groups were balanced with regard to median age (76 years in each), AML type (de novo, 75% vs. 76%; secondary, 25% vs. 24%), ECOG performance status (0 to 1, 55% vs. 56%), bone marrow blast count ( 50%, 49% in each), cytogenetic risk category (intermediate, 64% vs. 61%) and somatic mutations.
OS served as the primary endpoint. Secondary endpoints included rates of complete remission, a composite of complete remission plus complete remission with incomplete count recovery (CRi), transfusion independence, OS by molecular subgroup and EFS.
Median follow-up was 20.5 months.
The median number of treatment cycles was seven in the azacitidine- venetoclax group and 4.5 in the azacitidine-placebo group.
Researchers reported a statistically significant improvement in median OS among patients assigned azacitidine- venetoclax (14.7 months vs. 9.6 months; HR = 0.66; 95% CI, 0.52-0.85).
Results showed a higher composite of complete remission and CRi among venetoclax-treated patients (66.4% vs. 28.3%; P < .001), with median time to first complete remission or CRi response (1.3 months vs. 2.8 months) and median duration of response (17.5 months vs. 13.4 months) favoring the venetoclax group.
The azacitidine-venetoclax combination also induced higher response rates among patients with poor cytogenetic risk (53% vs. 23%) and intermediate cytogenetic risk (74% vs. 32%), as well as among patients with de novo AML (66% vs. 30%) and secondary AML (67% vs. 23%).
A higher percentage of patients assigned venetoclax than placebo experienced grade 3 or higher thrombocytopenia (45% vs. 38%), neutropenia (42% vs. 29%), febrile neutropenia (42% vs. 19%), anemia (26% vs. 20%) and leukopenia (21% vs. 12%). The 30-day mortality rate was comparable between groups (7% vs. 6%).
Three patients (1%) assigned venetoclax developed tumor lysis syndrome, compared with none in the placebo group.
“The adverse events with the azacitidine and venetoclax combination were similar to previously reported experiences,” DiNardo said during her presentation, noting the observed safety risks were managed with standard-of-care approaches. “Tumor lysis syndrome events resolved with medical interventions, allowing for continued therapy.”
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DiNardo CD, et al. Abstract AML-063. Presented at: Society of Hematologic Oncology Annual Meeting (virtual meeting); Sept. 9-12, 2020.
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