Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial
- 11 June 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 135 (24), 2137-2145
- https://doi.org/10.1182/blood.2020004856
Abstract
Background: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Methods: Adults ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international Phase 3 randomized, double-blind, placebo-controlled trial. Patients (N=211) were randomized 2:1 to either: venetoclax (N=143) or placebo (N=68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1-10. The primary endpoint was overall survival (OS); secondary endpoints included response rates, transfusion independence, and event-free survival. Results: Median age was 76 years (range 36-93), 38% had secondary AML, and 20% had prior hypomethylating agent (HMA) treatment. The planned primary analysis showed that the venetoclax arm provided a benefit of 25% reduction in the risk-of-death over the LDAC-alone arm (hazard ratio [HR] 0.75 [95% CI 0.52-1.07], p=0.11), although it was not statistically significant; with median OS of 7.2 months and 4.1 months, respectively. An unplanned analysis with an additional 6 months of follow up demonstrated a median OS of 8.4 months for the venetoclax arm (HR 0.70; 95% CI 0.50-0.98; p=0.04). The CR/CRi rates were 48% and 13% for the Venetoclax plus LDAC arm and LDAC-alone arm, respectively. Key grade ≥3 adverse events (Ven vs. LDAC-alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs. 16%), and thrombocytopenia (45% vs 37%). Conclusion: Venetoclax plus LDAC demonstrates a clinically meaningful improvement in remission rates and OS compared to LDAC alone, in the context of a manageable safety profile. These results confirm venetoclax plus LDAC is an important frontline AML treatment option for patients unfit for intensive chemotherapy.Keywords
This publication has 28 references indexed in Scilit:
- International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blastsBlood, 2015
- Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapyBlood, 2014
- Ex vivoactivity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignanciesLeukemia & Lymphoma, 2014
- BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem CellsCell Stem Cell, 2013
- Multicenter, Randomized, Open-Label, Phase III Trial of Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients With Newly Diagnosed Acute Myeloid LeukemiaJournal of Clinical Oncology, 2012
- The Tumor Lysis SyndromeThe New England Journal of Medicine, 2011
- Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia RegistryBlood, 2009
- A comparison of low‐dose cytarabine and hydroxyurea with or without all‐trans retinoic acid for acute myeloid leukemia and high‐risk myelodysplastic syndrome in patients not considered fit for intensive treatmentCancer, 2007
- Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid LeukemiaJournal of Clinical Oncology, 2003
- Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML)Blood, 2003