In November 2018, the U.S. Food and Drug Administration (FDA) rendered accelerated approval to venetoclax in combination with azacitidine or decitabine or low-dose cytarabine (LDAC) for the treatment of newly diagnosed acute myeloid leukemia (AML) in older patients (> 75 years) or patients with comorbidities that precluded the use of intensive induction chemotherapy.1 The approval was based on two early-phase, nonrandomized trials that showed better rates of complete remission (CR) and longer duration of remission when compared to historical rates of azacitidine, decitabine, or LDAC alone.2,3 The FDA’s continued approval, however, was to be dependent on two randomized phase III trials, VIALE-A and VIALE-C, that combined venetoclax with azacitidine or with low-dose cytarabine, respectively. Researchers powered the study to determine improvement in overall survival (OS) rate among patients who received the combination, compared to those who did not.
In the current article, Dr. Andrew H. Wei and colleagues report the results of the VAILE-C trial, which was designed for patients with newly diagnosed AML who were ineligible to receive intensive induction therapy. This trial was a randomized double-blind placebo-controlled phase III international study to evaluate whether the combination of venetoclax and LDAC improved the OS as compared to placebo and LDAC. The study was conducted across 76 international sites and enrolled 211 adult patients with a median age of 76 years (range, 36-93 years) between May 2017 and November 2018. Patients were randomized 2:1 to receive the interventional treatment, and the randomization was stratified by AML diagnosis (secondary vs. de novo), age (18 to < 75 years vs. > 75 years), and international region (United States, Europe, China, Japan, or rest of the world). Patients with secondary AML who had received prior treatment with hypomethylating agents for myelodysplastic syndrome were eligible for enrollment, but patients with secondary AML from antecedent myeloproliferative neoplasms were not.
The study treated 210 patients; 68 patients were randomized to the placebo plus LDAC arm, and 143 patients were randomized to the venetoclax and LDAC arm. The median OS for patients treated with venetoclax and LDAC was 7.2 months (95% CI, 5.6-10.1), as compared to 4.1 months (95% CI, 3.1-8.8) for patients treated with placebo and LDAC. The hazard ratio (HR) between the two treatments was 0.75 (95% CI, 0.52-1.07; p=0.11). The original statistical design assumed a median OS of 11 months for venetoclax and LDAC (vs. 6 months for venetoclax plus placebo; HR, 0.545) given that the median OS from the phase Ib/II trial was 10.1 months for the combination. On the basis of these findings, the study failed to meet the primary endpoint.
Peculiarly, since the primary survival endpoint was not reached, the authors performed additional analysis of the data, utilizing an additional six months of follow-up events. In this “unplanned” or “post-hoc” analysis, the median OS for patients treated with venetoclax and LDAC was 8.4 months, versus 4.1 months for patients in the placebo and LDAC arm. The HR for the post-hoc analysis was 0.70 (95% CI, 0.50-0.99) with a p value of 0.04.Also, an “unplanned” or “post-hoc” multivariate analysis was performed. The following baseline prognostic factors were identified as significantly associated with OS: AML status (de novo vs. secondary), cytogenetic risk (intermediate vs. poor), Eastern Cooperative Oncology Group performance status (<2 vs. >2), and age (< 7 5 vs. > 75 years). The adjusted HR for the venetoclax and LDAC arm was 0.67 (95% CI, 0.47-0.96; p=0.03).
Regarding the main secondary endpoints, the complete marrow response rate was 27 percent in the venetoclax and LDAC arm and 7 percent in the placebo and LDAC arm. The CR/CR with incomplete recovery (CRi) rate was 48 percent in the venetoclax and LDAC arm, and 13 percent in the placebo and LDAC arm. Reaching CR/CRi prior to cycle 2 of treatment was more likely in the venetoclax and LDAC arm as compared to placebo and LDAC (34% vs. 3%, respectively). The undetectable minimal residual disease rate (defined as a level < 0.1%) for patients in CR or CRi was 6 percent for the venetoclax and LDAC arm and 1 percent for the placebo and LDAC arm. Additionally, the rate of transfusion independence was increased in the venetoclax and LDAC arm versus placebo and LDAC (37% vs. 16%, respectively). Common grade 3 or greater adverse events (AEs) were related to myelosuppression (venetoclax and LDAC vs. placebo and LDAC) and included febrile neutropenia (32% vs. 29%), neutropenia (46% vs. 16%), and thrombocytopenia (45% vs. 37%). AEs leading to treatment discontinuation were similar between the treatment arms (25% vs. 24%). The 30-day mortality rates were similar in the venetoclax and LDAC arm and in the placebo and LDAC arm (13% and 16%, respectively). Finally, quality-of-life assessments were done, and these measures seemed similar between the two treatment groups.
Treatment of AML in older patients continues to be challenging, and effective therapeutic regimens are especially limited in older patients in whom intensive induction chemotherapy is unreasonable. Thus, the development of less intense and effective therapeutic regimens for older adults with AML has been a major research priority. The VIALE-C trial did not meet the primary survival endpoint as defined in the original statistical design, and the p value of the HR from the “post-hoc” analysis is meaningless. The data do show, however, that there may be a survival benefit to the combination of venetoclax and LDAC, but this benefit is more modest than expected based on the data from the phase Ib/II study. Nonetheless, these results still hold clinical relevance with improved response rates, transfusion independence, and a tolerable safety profile. The optimal safe therapeutic approach for AML in older adults who are unable to tolerate intensive induction chemotherapy remains subject to further investigation and refinement. Whether the FDA grants continued approval to the combination based on the reported results is uncertain.
Dr. Tbakhi and Dr. O’Dwyer indicated no relevant conflicts of interest.