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Venetoclax plus low-dose cytarabine confirms its clinically meaningful improvement in overall survival in previously untreated older acute myeloid leukaemia patients

The primary analysis of the phase III VIALE-C study demonstrated that adding venetoclax to low-dose cytarabine (LDAC) resulted in a 25% reduction in the risk of death for newly diagnosed acute myeloid leukaemia (AML) patients who were unfit for intensive chemotherapy. At EHA 2020, Wei et al. presented an updated analysis of this trial with an additional 6 months of follow-up. In this analysis, patients in the venetoclax arm were found to have a median overall survival (OS) of 8.4 months, which was more than twice as long as the 4.1 months median OS in placebo-LDAC arm. In addition, the venetoclax-LDAC combination was associated with significantly higher remission rates and responses to venetoclax-LDAC also proved to be more durable than the responses seen in the control arm. As such, these findings identify venetoclax plus LDAC as an important therapeutic option for this underserved patient population.

Background and study design

Venetoclax is a small-molecule BCL-2 inhibitor, with an established role in the treatment of patients with chronic lymphocytic leukaemia. More recently, this agent has been evaluated as a partner for hypomethylating agents or LDAC for patients with newly diagnosed AML. The primary focus in this respect consisted of older patients or patients with comorbidities precluding the use of intensive chemotherapy. The VIALE-C study was designed to compare the safety and efficacy of venetoclax or placebo plus LDAC in previously untreated patients with AML. The initial primary analysis of the VIALE-C study with a median follow-up of 12 months demonstrated a clinically meaningful improvement in the median OS from 4.1 months with placebo + LDAC to 7.2 months with venetoclax + LDAC. At that timepoint, however, this OS difference did not yet meet the threshold for statistical significance (HR [95%CI]: 0.75 [0.52-1.07], p=0.11).

In order to be eligible for the VIALE-C study patients had to be 75 years or older, or have comorbidities precluding intensive chemotherapy (age >18 years). In total, 211 patients were enrolled in the study and randomised (2:1) to venetoclax (600 mg orally once daily on days 1-28 with a 4-day ramp-up in first the cycle) or placebo in 28-day cycles, both in combination with LDAC (20 mg/m2 subcutaneously once daily on days 1 to 10). Patients could continue receiving treatment until progression or until study treatment discontinuation criteria were met. The median age of patients in the study was 76 years in both arms and one fifth previously received a hypomethylating agent. Baseline characteristics were well balanced between both treatment arms except for a higher percentage (41%) of secondary AML in the venetoclax arm, as compared to the placebo arm (34%).


After a median follow-up of 17.5 months, patients in the venetoclax-LDAC experienced a 30% reduction in the risk of death compared to patients in the control arm. The median OS for patients in the venetoclax-LDAC arm was 8.4 months, compared to 4.1 months for patients treated with placebo-LDAC (HR [95%CI]: 0.704 [0.50-0.99], p=0.040). The addition of venetoclax to LDAC also resulted in a significant increase in the proportion of patients obtaining a complete remission (CR) from 7% to 28% (p<0.001). If also patients with a CR and incomplete blood count recovery were considered, the difference was even more pronounced with a CR/CRi rate of 48% for venetoclax-LDAC and 13% for placebo-LDAC (p<0.001). Importantly, the responses that were obtained with venetoclax-LDAC were also more durable than the responses seen with placebo-LDAC, reflected by a median duration of response of 17 and 8 months, respectively. In addition, also the red blood cell transfusion independence rate (43% versus 19%, p<0.001) and platelets transfusion independence rate (49% versus 32%, p=0.024) were in favour of the venetoclax plus cytarabine combination. Finally, patients treated with venetoclax had a median event-free survival of 4.9 months, this was only 2.1 months for patients in the placebo group (HR [95%CI]: 0.61 [0.44–0.84], p= 0.002).

Further subgroup analyses of the trial revealed that the most impressive CR/CRi rates were observed in patients aged ≥75 years (50.0%), patients with intermediate cytogenetic risk (56.7%) and patients harbouring NPM1 mutations (78.9%). In terms of OS, the subgroup analysis indicated that patients with intermediate cytogenetic risk or NPM1 mutations seemed to benefit most from venetoclax.

The most common grade ≥ 3 adverse events (AEs) in the venetoclax arm were neutropenia (49%), thrombocytopenia (46%) and febrile neutropenia (32%). The most common serious AEs were febrile neutropenia (17%) and pneumonia (14%). Tumour lysis syndrome occurred in 5.6% of the patients in the venetoclax arm and in none of the patients treated in the placebo arm, indicating that this remains a risk that necessitates appropriate monitoring and prophylaxis. Early death within 30 days of the first dose of study drug occurred in 13% of patients in the venetoclax + LDAC arm versus 16% in the placebo + LDAC arm. Treatment-emergent AEs leading to death happened in 23% of the patients in the venetoclax arm as compared to 21% of the patients in the placebo arm. Intensive post-study chemotherapy was administered to 22% of the patients treated with placebo and to only 8% of the patients treated with venetoclax.


In newly diagnosed AML patients who are deemed unfit for intensive chemotherapy, the combination of venetoclax and LDAC was found to induce a clinically meaningful OS improvement compared to placebo plus LDAC. Importantly, the treatment regimen was well tolerated and came with a manageable safety profile. Additional benefits of venetoclax include a higher rate of more durable complete remissions, a longer event-free survival and higher rates of transfusion independence. These data further support the venetoclax-LDAC combination as a frontline treatment option for older patients with AML, as well as for patients who are considered to be unfit for intensive chemotherapy.


Wei AH, Montesinos P, Ivanov V, et al. A phase 3 study of venetoclax plus low-dose cytarabine in previously untreated older patients with acute myeloid leukemia (VIALE-C): a 6-month update. Presented at EHA 2020; Abstract S136.

Speaker Andrew Wei


Andrew H. Wei, MBBS, FRACP, FRCPA, PhD, The Alfred Hospital, Melbourne, Australia


See: Keyslides


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