Conference Coverage

VIALE-A confirms survival benefit for venetoclax-azacitidine in hard-to-treat AML



Adding venetoclax to azacitidine significantly extended survival of patients with previously untreated acute myeloid leukemia (AML) who were ineligible for standard induction therapy, results of the phase 3 VIALE-A trial showed.

Median overall survival for patients treated with venetoclax (Venclexta) and azacitidine was 14.7 months, compared with 9.6 months for patients who received azacitidine with a placebo, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“The combination of [azacitidine] and [venetoclax] was associated with statistically significant and clinically meaningful improvements in overall survival, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML,” she said in a late-breaking abstract presentation at the virtual annual congress of the European Hematology Association.

Patients with newly diagnosed AML who are aged 75 years and older or have significant comorbidities are often not able to withstand the rigors of standard induction therapy for AML and have instead been treated with low-dose hypomethylating agents or cytarabine, but these therapies typically are associated with inferior outcomes, Dr. DiNardo said.

Venetoclax has shown good single-agent activity against relapsed/refractory AML. Early efficacy results of a phase 1b study, reported at the 2017 EHA Congress, showed that, among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall response rate, and that older patients were able to tolerate the regimen.

No surprise

The results of the VIALE-A study merely confirm what hematologists/oncologists have known for several years, said Joshua F. Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“Most leukemia clinicians have been using this regimen as a standard of care prior to these results,” he said in an interview. Dr. Zeidner was not involved in the study.

In November 2018, the Food and Drug Administration granted accelerated approval to venetoclax in combination with either azacitidine or decitabine or low-dose cytarabine in adults with newly diagnosed AML who because of age or comorbidities were ineligible for standard intensive induction regimens. Dr. Zeidner noted, however, that there are still questions about the combination in this population that need further exploration.

Despite being labeled as a “low-intensity” therapy, “I think low intensity is sort of a misnomer here,” he said. “It’s very challenging to give this regimen in the community because of all of the cytopenias, a high degree of transfusion dependence that these patients have, at least in the first few cycles, and all the rigorous laboratory monitoring and drug interactions that are common with venetoclax really lead to a lot of challenges in the community.”

Also still unanswered are questions about how to dose patients with early responses who have potential dose-limiting toxicities such as neutropenia and thrombocytopenia, he said.

It’s also unclear whether patients will require hospitalization during the ramp-up phase of venetoclax, as was done in some clinical trials, because of risk of tumor lysis syndrome. In the VIALE-A study, however, there were only three minor biochemical cases of tumor lysis syndrome in the experimental arm, and none of these cases required dose modification or treatment discontinuation.

“This begets the question whether patients need to be hospitalized at for the initiation of this treatment,” Dr. Zeidner said. Additional studies will also be needed to see whether certain subgroups of patients would be likely to derive particular benefit from venetoclax plus azacitidine, such as patients with IDH1 or IDH2 somatic mutations.


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