Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy

威尼斯人 阿扎胞苷 医学 髓系白血病 化疗方案 内科学 化疗 白血病 肿瘤科 生物 遗传学 基因 基因表达 DNA甲基化 慢性淋巴细胞白血病
作者
Keith W. Pratz,Brian A. Jonas,Vinod Pullarkat,Michael J. Thirman,Jacqueline S. Garcia,Walter Fiedler,Kazuhito Yamamoto,Jianxiang Wang,Sung-Soo Yoon,Ofir Wolach,Jun‐Ho Jang,Su‐Peng Yeh,Grace Ku,Ying Zhou,Brenda Chyla,Jalaja Potluri,Courtney D. DiNardo
出处
期刊:Blood [Elsevier BV]
卷期号:140 (Supplement 1): 529-531 被引量:36
标识
DOI:10.1182/blood-2022-158518
摘要

Background: Venetoclax (Ven), a highly selective oral BCL-2 inhibitor, in combination with azacitidine (Aza) is approved for the treatment of patients with intensive chemotherapy-ineligible newly diagnosed AML based on the positive results of the phase 3 VIALE-A study (NCT02993523) of placebo (Pbo) vs Ven in combination with Aza in this population (DiNardo et. al. NEJM, 2020). At a median follow-up of 20.5 (range, <0.1-30.7) months (mo), with 270 death events (75% OS) in January 2020, the median overall survival (OS) was 14.7 mo for the Ven+Aza group and 9.6 mo in the Pbo+Aza group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). Complete remission (CR) was higher with Ven+Aza than with Pbo+Aza (36.7% vs 17.9%; P<0.001), as was complete remission + complete remission with incomplete hematologic recovery (CR+CRi) (66.4% vs 28.3%; P<0.001) (DiNardo et. al. NEJM, 2020). While the study met the statistical significance for its primary endpoint of overall survival at the 75% OS interim analysis in March 2020, with 270 OS events, a 100% final OS analysis was undertaken with 360 survival events (data cut-off of 01 December, 2021), with 2-years of additional follow-up to determine the long-term survival benefit of Ven+Aza. Here, we present the analysis of VIALE-A, after the occurrence of 100% of the pre-planned survival events. Methods: 431 patients with confirmed AML who were previously untreated and ineligible for intensive therapy were randomly assigned 2:1 to Aza plus either Ven (286 patients) or Pbo (145 patients). All patients received a standard dose of Aza (75 mg/m2 subcutaneously or intravenously on days 1 through 7 every 28-day cycle). Ven 400 mg after a 3 day ramp up to reach the target dose in Cycle 1 or a matching Pbo was administered orally, once daily, in 28-day cycles. Results: Median age was 76 years in both groups, approximately 60% were male and 76% were Caucasian. Molecular abnormalities of interest included FLT-3, observed in 14.1% of patients receiving VEN+AZA, IDH1/2, observed in 24.9% of pts, TP53, observed in 23.3% of pts and NPM1, observed in 16.6% of pts. With a median follow-up of 43.2 mo, the median overall survival was 14.7 mo (95% CI, 12.1 to 18.7) in the Ven+Aza group and 9.6 mo (95% CI, 7.4 to 12.7) in the Pbo+Aza group (HR, 0.58; 95% CI, 0.47 to 0.72; nominal P<0.001), maintaining the survival benefit since the interim analysis in the overall population (Figure 1). At this data-cut, 49 pts remained on the study (48 in the Ven+Aza group and 1 in the Pbo+Aza group). In patients with measurable residual disease (MRD) <10-3 who had achieved CR+CRi, median OS was reached at 34.2 mo (95% CI, 27.7-44.0) in the Ven+Aza group (N=69) and 25.0 mo (95% CI, 7.0-39.8) in the Pbo+Aza group (N=11). In CR + CRi patients with MRD >10-3, median OS was 18.7 mo (95% CI, 12.9-23.5) in the Ven+Aza group (N=96) and 15.1 mo (95% CI, 7.4, 26.1) in the Pbo+Aza group (N=24). For patients in the IDH1/2 mutant subgroup, median OS was reached at final analysis, at 19.9 mo (95% CI, 12.2-27.7) in the Ven+Aza group and 6.2 mo (95% CI, 2.3-12.7) in the Pbo+Aza group (HR, 0.314; 95% CI, 0.189 to 0.522; P<0.001) (Figure 2). Overall safety profiles were comparable between Ven+Aza and Pbo+Aza. Key treatment-emergent adverse events of any grade occurring in ≥20% of pts included nausea (44.5% in the Ven+Aza group vs 36.8% in the Pbo+Aza group), diarrhea (45.2% vs 34%), and constipation (43.8% vs 39.6%). Grade 3 or higher AEs (Ven+Aza vs Pbo+Aza) occurring in ≥10% of pts included thrombocytopenia (45.9% vs 39.6%), neutropenia (42.8% vs 28.5%), and febrile neutropenia (42.8% vs 18.8%). Serious adverse events occurred in 85.1% of pts in the Ven+Aza group and 77.1% of those in the Pbo+Aza group. Further characterization of pts with long term benefit is ongoing. Conclusions: The VIALE-A long-term follow up demonstrates sustained overall survival benefit with Ven+Aza in patients with AML ineligible for intensive chemotherapy compared to Pbo+Aza in all subgroups. Notably, the median OS for patients with MRD <10-3 who had achieved CR+CRi was 34.2 mo, and median OS for patients with IDH1/2 mutations treated with Ven+Aza was 19.9 mo. The VIALE-A 2-year follow-up analysis confirms the long-term survival benefit for patients treated with Ven+Aza, with no new safety findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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