-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

219 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: New Approaches to Combination Chemotherapy and Venetoclax Plus Hypomethylating Agent Therapy in AML
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, adult, Clinical Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies, Study Population, Human, Minimal Residual Disease
Saturday, December 10, 2022: 2:30 PM

Keith W. Pratz, MD1, Brian A. Jonas, MD, PhD2, Vinod A. Pullarkat, MD3*, Michael J. Thirman, MD4, Jacqueline S. Garcia, MD5, Walter Fiedler, MD6, Kazuhito Yamamoto, MD, PhD7, Jianxiang Wang, MD8, Sung-Soo Yoon, MD, PhD9, Ofir Wolach, MD10*, Jun-Ho Jang, MD11*, Su-Peng Yeh, MD12*, Grace Ku, MD13, Ying Zhou, PhD14*, Brenda Chyla, PhD14, Jalaja Potluri, MD14 and Courtney D. DiNardo, MD, MSCE15

1Division of Hematology and Oncology, Abramson Cancer Center University of Pennsylvania, Philadelphia, PA
2Department of Internal Medicine, Division of Malignant Hematology, Transplantation and Cellular Therapy, University of California Davis School of Medicine, Sacramento, CA
3Department of Hematology and Hematopoietic Cell Transplantation and Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte, CA
4Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
6Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, University Hospital Eppendorf, Hamburg, Germany
7Aichi Cancer Center, Nagoya, Japan
8Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
9Division of Hematology/Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of (South)
10Rabin Medical Center, Petah Tikva, Israel
11Division of Hematology-Oncology, Samsung Medical Center, Seoul, Korea, Republic of (South)
12China Medical University Hospital, Taichung, Taiwan
13Genentech, South San Francisco, CA
14AbbVie Inc., North Chicago, IL
15Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

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.

Disclosures: Pratz: AbbVie, Astellas, Boston BioMedical, BMS, Celgene, Novartis, Jazz Pharmaceuticals, and Servier.: Membership on an entity's Board of Directors or advisory committees; AbbVie, Agios, Daiichi Sankyo, Millennium: Research Funding. Jonas: Pfizer: Consultancy, Research Funding; 47: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Other: data monitoring committee , Research Funding; Jazz: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: protocol steering committee , Research Funding; Servier: Consultancy; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Accelerated Medical Diagnostics: Research Funding; Amgen: Research Funding; AROG: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Roche: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; LP Therapeutics: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding; AbbVie: Consultancy, Other: Travel Reimbursement, Research Funding; Rigel: Consultancy, Other: Travel Reimbursement. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen, Dova, and Novartis: Consultancy, Other: Advisory Board Member. Thirman: AbbVie, AstraZeneca, Celgene,Janssen, Pharmacyclics, Roche/Genentech: Consultancy; AbbVie,Gilead Sciences,Janssen,Merck,Pharmacyclics, Syndax, TG Therapeutics, Tolero Pharmaceuticals.: Consultancy, Research Funding. Garcia: AbbVie, Genentech, AstraZeneca, Prelude and Pfizer: Other: Clinical trial support (institutional) , Research Funding; AbbVie, Astellas, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board ; AbbVie: Research Funding. Yamamoto: Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Micron/Daiichi-Sankyo: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria; Takeda: Honoraria, Research Funding; SymBio: Honoraria, Research Funding; Astra-Zeneca: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Sumitomo Pharma: Honoraria; IQVIA/Incyte: Honoraria; HUYA/IQVIA Services Japan: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria; Solasia Pharma: Research Funding; Sanofi: Honoraria; Zenyaku: Research Funding; Yakult: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; MSD: Honoraria; Janssen: Honoraria; Eisai: Honoraria, Research Funding; Astellas: Honoraria; AbbVie: Honoraria, Research Funding; IQVIA/Genmab: Honoraria. Wang: AstraZeneca: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yoon: Roche-Genetech: Research Funding; Yuhan Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Astellas Pharma: Consultancy; Celgene: Consultancy; Janssen Pharmaceutical: Consultancy; Takeda: Consultancy; Tikaros: Consultancy; Chugai Pharmaceutical: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Wolach: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jansen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jang: AbbVie: Research Funding. Yeh: AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda Oncology: Membership on an entity's Board of Directors or advisory committees. Ku: Genentech: Current Employment, Current equity holder in publicly-traded company. Zhou: AbbVie: Current Employment, Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Potluri: AbbVie: Current Employment, Current equity holder in publicly-traded company. DiNardo: Cleave: Research Funding; Astex: Research Funding; LOXO: Research Funding; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Foghorn: Honoraria, Research Funding; Astellas: Honoraria; Forma: Research Funding; Bluebird Bio: Honoraria; Servier: Consultancy, Honoraria, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria.

*signifies non-member of ASH