FDA Approves Venetoclax Plus LDAC For Older Patients With Newly Diagnosed AML

October 16, 2020
Nichole Tucker

Nichole Tucker, MA, is the Web Editor for Targeted Oncology. Tucker received her Bachelor of Arts in Mass Communications from Virginia State University and her Master of Arts in Media & International Conflict from University College Dublin.

The FDA granted approval to venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine, a regimen known as LDAC, as treatment of adults patients with aged 75 years or older with newly-diagnosed acute myeloid leukemia or who have comorbidities precluding intensive induction chemotherapy.

The FDA granted approval to venetoclax in combination with azacitidine (Vidaza), decitabine (Dacogen), or low-dose cytarabine, a regimen known as LDAC, as treatment of adults patients with aged 75 years or older with newly-diagnosed acute myeloid leukemia (AML) or who have comorbidities precluding intensive induction chemotherapy.1

Single-agent venetoclax previously received approval for this indication.

Approval was granted based on the positive results from the confirmatory VIALE-A (NCT02993523) and the VIALE-C (NCT03069352) clinical trials.

VIALE-A was a randomized, placebo-controlled study. Randomization in the study was 2:1. In the venetoclax combination arm, 286 patients were enrolled, and in the 145 patients were enrolled in the placebo plus azacitidine group. Patients were evaluated on treatment with either combination for the primary end point of overall survival. As secondary end points, the study assessed composite complete remission, complete remission with or without partial hematologic recovery, complete remission by the initiation of cycle 2, red-cell and platelet transfusion independence, composite complete remission and overall survival in molecular and cytogenetic subgroups, event-free survival, measurable residual disease, and quality of life per patient-reported outcomes.2

The trial was 86.7% power to detect a hazard ratio of 0.70 utilized a log-rank test at a two-sided significance level of 0.04.

At a median follow-up of 20.5 months (range, <0.1-30.7), the median OS was 14.7 months (95% CI, 11.9-18.7) in the venetoclax arm versus 9.6 months (95% CI, 7.4-12.7) in the control arm (HR, 0.66; 95% CI, 0.52-0.85; P <.001).

Treatment with the venetoclax-containing regimen led to a composite complete remission rate of 66.4% (95% CI, 60.6-71.9) compared with 28.3% (95% CI, 21.1-36.3) in the control arm, (P <0.001). Before the initiation of cycle 2, the composite complete remission rate was 43.4% (95% CI, 37.5-49.3) in the venetoclax arm versus 7.6% (95% CI, 3.8 to 13.2) in the control arm (P <.001).

It was observed that the median time to first response was 3 months (range, 0.6-9.9) with LDAC compared with 2.8 months (range, 0.8 to 13.2) with placebo plus azacitadine. The median duration of complete remission for the venetoclax and control arms 17.5 months (95% CI, 13.6 to not reached [NR]) versus 13.4 months (95% CI, 5.8-15.5), respectively.

Complete remissions were seen in 36.7% of the LDAC arm and 17.9% of the control arm, ( P

Complete remission was achieved in 36.7% and 17.9% of the patients, respectively (P <.001). The median duration of these responses was 17.5 months (95% CI, 15.3-NR) versus 13.3 months (95% CI, 8.5-17.6), respectively. The complete remission with hematologic recovery end point showed similar efficacy with a rate of 64.7% (95% CI, 58.8-70.2) in the LDAC arm compared with 22.8% (95% CI, 16.2 to 30.5) in the control arm (P< .001).

Across the other secondary end points, all results favored the LDAC regimen over placebo and azacitidine.

VIALE-C is an ongoing phase 3 randomized, double-blind, placebo-controlled trial 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.3

A 6-month update from the study was presented at the 2020 American Society of Oncology Virtual Annual Meeting, a showed clinically meaningful improvement in OS compared with venetoclax plus LDAC versus placebo plus LDAC.

The median OS observed in the study was 8.4 months compared with 4.1 months in the placebo arms (HR 0.70; 95% CI 0.50-0.99; P= .04), demonstrating a 30% reduction in the risk of death in the population of 210 patients. Based on these 6-month findings, the study authors led by Andrew H. Wei, MD concluded that venetoclax plus LDAC is supported as a frontline treatment option for older patients with AML.

According to data from both clinical trials, venetoclax plus LDAC, the most common adverse reactions that occurred in ≥ 30 of patients who received venetoclax plus LDAC included nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.1

The FDA review of the application for approval regarding venetoclax plus LDAC in adults patients aged 75 years or older with newly-diagnosed acute myeloid leukemia or who have comorbidities precluding intensive induction chemotherapy was completed through Project Orbis, an FDA Oncology Center of Excellence imitative to streamline regulatory decisions worldwide. The application was also reviewed through the Real-Time Oncology Review process.


1. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. News release. FDA. October 16, 2020. Accessed October 16, 2020. https://bit.ly/3o0CBPl

2. DiNardo CD, Jonas BA, Pullarkat MJ, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-29. doi: 10.1056/NEJMoa2012971

3. Wei AH, Monteinos P, Ivanov V, et al. 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. 2020;38 (suppl 15 ): 7511-7511. doi: 10.1200/JCO.2020.38.15_suppl.7511