There are two pivotal publications exploring the utility of low dose cytarabine (LDAC) and venetoclax in combination for acute myeloid leukaemia (AML) in patients not suitable for intensive induction chemotherapy.
Firstly, an international phase Ib/II study evaluating safety and preliminary efficacy of venetoclax with LDAC in older adults (≥60 years) with previously untreated AML and ineligible for intensive chemotherapy (n=82).r Patients were treated with venetoclax 600 mg daily (Day 1 to 28) and LDAC 20 mg/m2 (Day 1 to 10). The study included patients with prior treatment of myelodysplastic syndrome (MDS), including hypomethylating agents (HMA). Key endpoints were tolerability, safety, response rates, duration of response, and overall survival (OS). Median age was 74 (63 to 90 years), 49% had secondary AML, 29% had prior HMA, and baseline mutations in p53, FLT3, IDH1/2, and NPM1 were detected in 14%, 23%, 25%, and 13% of patients, respectively.
Secondly, an international phase III randomised, double-blind placebo-controlled trial for newly diagnosed patients with AML (age >18 years, median age 76 years) not suitable for intensive induction chemotherapy (VIALE-C).r In this study, 211 patients were randomised 2:1 to venetoclax 600 mg daily (D1-28) plus LDAC 20 mg/m2 (Day 1 to 10) or placebo plus LDAC. The primary endpoint was OS, with key secondary endpoints including, response rate, transfusion independence, and event-free survival (EFS). Similar to the phase Ib/II study, 38% had secondary AML, and 20% had received prior HMA treatment. Baseline mutations in p53, FLT3, IDH1/2, or NPM1 were detected in 15%, 14%, 16%, and 12% of patients respectively. Patients were stratified for analysis by baseline intermediate or poor cytogenetic risk, mutations in p53, IDH1/2, FLT3, or NPM1, and other key baseline prognostic factors.
In the phase Ib/II study, the complete remission (CR) plus complete remission with incomplete blood count recover (CRi) rate was 54% with median time to first CR/CRi 1.4 months (range, 0.8 to 14.9 months). Patients with de-novo AML (CR/CRi 71%), intermediate-risk cytogenetics (CR/CRi 63%) and without prior HMA exposure (CR/CRi 62%) had the highest rates of CR/CRi. For patients achieving CR/CRi after venetoclax plus LDAC, the median duration of remission was 8.1 months (95% CI, 5.3 to 14.9 months). The median OS for all patients was 10.1 months (95% CI, 5.7 to 14.2 months). Survival was better for patients achieving CR/CRi, and patients with no response had poor outcomes (Figure 1). Patients without prior HMA exposure had a longer median OS than patients previously treated with HMA (13.5 months vs 4.1 months). Patients with mutations in NPM1 or IDH1/2 had above average CR/CRi rates (89% and 72%, respectively), whereas those with p53 or FLT3 mutations had lower CR/CRi rates (30% and 44%), respectively.r
Figure 1: Overall survival based on response in the phase Ib/II studyr
© Journal of Clinical Oncology 2019
In the phase III trial, pre-planned analysis at 12 months (Figure 2A) showed 40% (57 of 143) and 31% (21 of 68) of patients remained alive in the venetoclax and placebo arms, respectively. Median OS for patients treated with venetoclax plus LDAC was 7.2 months vs. 4.1 months for the placebo plus LDAC, with a hazard ratio (HR) (venetoclax vs. placebo) of 0.75 (95% CI, 0.52-1.07). Additional follow up at 18 months (Figure 2B) showed majority of patients passed the median OS in both arms (8.4 months for venetoclax plus LDAC vs 4.1 months for placebo plus LDAC). HR between venetoclax vs placebo treatment arms after this additional follow-up was 0.70 (95% CI, 0.50-0.99, p=0.04).r
Figure 2: Overall survival in the phase 3 trialr
© Blood 2020
Post-hoc analysis of variables revealed significant factors associated with response to venetoclax. CR/CRi and CR was achieved in 48% and 27% of patients receiving venetoclax, compared to 13% and 7% in the placebo arm. Responses in the venetoclax arm were faster, with higher remission rates accompanied by a longer median EFS (4.7 months vs. 2 months). Rates of transfusion independence were higher for venetoclax-treated patients compared to those receiving LDAC alone (37% vs. 16%). Patient subgroups with NPM1- (median OS not reached) and IDH1/2-mutant AML (median OS 19.4 months) demonstrated promising survival outcomes.r
The most common grade 3 or 4 adverse events (AEs) in the phase Ib/II study were haematological including febrile neutropenia (42%), thrombocytopenia (38%), neutropenia (27%), and anaemia (27%). The most common non-haematological AEs of any grade or cause were nausea (70%), diarrhoea (49%), hypokalaemia (48%), and fatigue (43%).r
The phase III trial demonstrated similar safety outcomes. Median dose intensity was similar in both arms and 99% of patients in both arms experienced 1 or more AE. The most frequent ≥ grade 3 AEs were febrile neutropenia, neutropenia, thrombocytopenia and anaemia. The most common non-haematological AEs of any grade were nausea, hypokalaemia, diarrhoea and constipation. Serious adverse events (SAE), of any grade, were reported in 66% (venetoclax arm) and 62% (placebo arm) of patients. There was a higher percentage of ≥ grade 3 bleeding AEs in the venetoclax arm, although the incidence of fatal bleeding was similar in both arms (1.4% vs. 1.5%). 8 patients (6%) in the venetoclax arm developed TLS (4 clinical, 4 laboratory) and 2 of these were SAEs related to TLS despite receiving TLS prophylaxis according to the protocol.r
Treatment emergent AEs by frequencyr
© Blood 2020