Commentary on VIALE-A Study

Dr Ng Chin Hin,
Senior Consultant Haematologist, CFCH
Former Head of Adult Leukaemia Service, National University Cancer Institute, Singapore
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A new standard of care for newly diagnosed elderly and unfit AML
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AML has a median age of around 65 years old, and many older patients have comorbidities, making them unsuitable for intensive chemotherapy. The current standard of care for older and unfit AML patients includes drugs such as low dose cytarabine or hypomethylating agents (azacitidine or decitabine) with complete response rates of less than 10% and 20-30% respectively..

Venetoclax, a highly specific oral BCL-2 inhibitor, has limited activity when given as a single agent but has shown promising clinical activity when used in combination with HMA or cytarabine in phase 2 studies. On November 21, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to venetoclax (Venclexta) together with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukaemia (AML) in adults who are age 75 years or older or who have comorbidities that preclude the use of intensive induction chemotherapy..

VIALE-A is the confirmatory phase 3 study comparing Venetoclax plus Azacitidine (Ven+Aza) versus Azacitidine (Aza) in newly diagnosed elderly AML age 75 years and above or those who are unfit for intensive chemotherapy. A total of 433 patients were randomised at 2:1 fashion with 286 patients on Ven+Aza arm and 145 patients on Aza arm..

The primary endpoint was overall survival, while secondary endpoints include response rate, transfusion independence rate and event-free survival. The median age was 76 years old. Poor risk cytogenetic constituted 36% and 39% of the Ven+Aza and Aza arms, respectively. TP53 mutations were present in 23% of Ven+Aza arm compared to 16% in Aza arm. At a median follow-up of 20.5 months, the overall survival of Ven+Aza was 14.7 months (95%CI: 11.9-18.7) while Aza was 9.6 months (95%CI: 7.4-12.7), with a hazard ratio of 0.66 (95%CI: 0.52-0.85), p<0.001. The overall survival benefit was seen across different subgroups and most prominently in IDH1/2 mutated AML..

The composite response rate (CR+CRi) was 66.4% and 28.3% in Ven+Aza and Aza arms, respectively. The median time to composite response was 1.3 months and 2.8 months, respectively. The duration of response was also significantly longer in Ven+Aza treated patients. In patients with IDH1/2 mutation, the incidence of composite remission was 75.4%. Interestingly, the response rate among FLT3 mutations was more than 70% as well. TP53 mutated AML showed a respectable composite remission of 55.3%. About 50% of the Ven+Aza treated patients were converted to platelet and red cells transfusion independence for more than eight weeks..

Addition of Venetoclax to the standard Azacitidine therapy significantly improves the overall response rate across different subgroups of AML patients. This translates to substantially longer overall survival in older unfit AML, even in subgroups of elderly AML patients with poor risk cytogenetic and TP53 mutation. The VIALE-A Study findings support the use of venetoclax + azacitidine as a new standard of care for newly diagnosed elderly and unfit AML.
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