The FDA has now granted full approval to venetoclax (Venclexta®, AbbVie Inc. and Genentech Inc.) in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC) for patients with previously untreated acute myeloid leukemia (AML) who are at least 75 years of age or who have comorbidities that prevent them from receiving intensive induction chemotherapy. Previously, this venetoclax combination therapy was granted accelerated approval in 2018 for use in this same patient population.
The approval was based on two phase 3 clinical trials: VIALE-A (NCT02993523) and VIALE-C (NCT03069352).
VIALE-A enrolled 431 patients with newly diagnosed AML who were ineligible for standard induction chemotherapy due to older age or comorbidities. Patients were randomized to receive 75 mg/m2 azacitidine with either 400 mg venetoclax once daily or placebo, for a primary end point of overall survival.
At a median follow-up of 20.5 months, venetoclax/azacitidine produced a higher median overall survival compared with placebo/azacitidine (14.7 vs 9.6 months). Patients receiving venetoclax/azacitidine also experienced higher rates of complete remission (36.7% vs 17.9%) and of composite complete remission, defined as complete remission or complete remission with incomplete hematologic recovery (66.4% vs 28.3%). Regarding adverse events, a higher proportion of patients receiving venetoclax/azacitidine experienced nausea (44% vs 35%), grade ≥3 thrombocytopenia (45% vs 38%), neutropenia (42% vs 28%), febrile neutropenia (42% vs 19%), and infections (84% vs 67%). Serious adverse events occurred in 83% of patients in the venetoclax/azacitidine group, compared with 73% of patients in the placebo/azacitidine group.
"In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone," commented the investigators of the study, led by first author Courtney D. DiNardo, MD, of the Department of Leukemia at MD Anderson Cancer Center.
VIALE-C enrolled 211 patients with previously untreated AML who were at least 75 years old or who had comorbidities precluding intensive induction chemotherapy. Patients were randomized in a 2:1 ratio to receive 20 mg/m2 LDAC in combination with either 600 mg venetoclax once daily or placebo. The primary end point was overall survival, with secondary end points of response, red blood cell and platelet transfusion independence, and event-free survival.
At a median follow-up of 17.5 months, venetoclax/LDAC produced a median overall survival of 8.4 months, compared with 4.1 months for placebo/LDAC, representing a 30% reduction in the risk of death. Venetoclax/LDAC also produced higher rates of complete remission (48% vs 13%), complete remission with partial hematologic recovery (48% vs 15%), red blood cell transfusion independence (43% vs 19%), platelet transfusion independence (49% vs 32%), and median event-free survival (4.9 vs 2.1 months) compared with placebo/LDAC. Grade ≥3 adverse events experienced by a higher proportion of patients receiving venetoclax included neutropenia (49% vs 18%), thrombocytopenia (45% vs 38%), and febrile neutropenia (32% vs 29%). Serious adverse events occurring in at least 10% of patients included febrile neutropenia (17% vs 18%) and pneumonia (14% vs 10%). Tumor lysis syndrome occurred in 5.6% of patients in the venetoclax/LDAC group and in none of the patients in the placebo/LDAC group.
"Venetoclax/LDAC demonstrates a clinically meaningful improvement in overall survival compared with placebo/LDAC, with a tolerable and manageable safety profile," commented the investigators of VIALE-C in their presentation abstract from the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, led by first author Andrew H. Wei, MBBS, PhD, Head of Leukemia Research at The Alfred Hospital in Melbourne, Australia. "These data support venetoclax/LDAC as a frontline treatment option for older patients with AML, as well as those considered unfit for intensive chemotherapy."
The recommended dosing schedule of venetoclax is 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3, followed by 600 mg once daily when in combination with LDAC or 400 mg once daily when in combination with azacitidine. Venetoclax should be administered in combination with 75 mg/m2 azacitidine once daily on Days 1-7, 20 mg/m2 decitabine once daily on Days 1-5, or 20 mg/m2 LDAC once daily on Days 1-10 of each 28-day cycle, until disease progression or unacceptable toxicity.
All patients receiving venetoclax should be given anti-hyperuricemic premedication for tumor lysis syndrome (TLS), and adequate hydration should be ensured.
For More Information
DiNardo CD, Jonas BA, Pullarkat V, et al (2020). Azacitidine and venetoclax in previously untreated acute myeloid leukemia. New Engl J Med, 383:617-629. DOI:10.1056/NEJMoa2012971
Wei AH, Montesinos P, Ivanov V, et al (2020). A phase III study of venetoclax plus low-dose cytarabine in previously untreated older patients with acute myeloid leukemia (VIALE-C): a six-month update. J Clin Oncol (ASCO Virtual Scientific Program Abstracts), 38(suppl_15). Abstract 7511. DOI:10.1200/JCO.2020.38.15_suppl.7511
Clinicaltrials.gov (2020). A study of venetoclax in combination with azacitidine versus azacitidine in treatment naive subjects with acute myeloid leukemia who are ineligible for standard induction therapy. NLM identifier: NCT02993523.
Clinicaltrials.gov (2020). A study of venetoclax in combination with low dose cytarabine versus low dose cytarabine alone in treatment naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy. NLM identifier: NCT03069352.
US Food & Drug Administration (2020). FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-regular-approval-venetoclax-combination-untreated-acute-myeloid-leukemia#:~:text=On%20October%2016%2C%202020%2C%20the,older%2C%20or%20who%20have%20comorbidities
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