Venetoclax plus low-dose cytarabine for AML: results of a phase III trial

Many patients with acute myeloid leukemia (AML) are not able to have intensive chemotherapy, as a result of comorbidities. Reduced intensity chemotherapy (RIC) regimens often used for these patients have limited success, with complete recovery (CR) and CR with incomplete blood count recovery (CRi) rates of < 30% with azacitidine or decitabine, and 11–19% with low-dose cytarabine (LDAC).¹ B-cell leukemia/lymphoma-2 (BCL2) family members are known to play a role in cell survival of cancer cells, and in chemoresistance. Venetoclax is a BCL2 inhibitor which has been assessed as a mono- and combination-therapeutic option in several hematological malignancies. Resistance to venetoclax is thought to be due to other BCL2 family proteins that suppress the effects of venetoclax, but may be overcome by the use of cytotoxic drugs such as cytarabine.

Andrew Wei and team recently published their phase III trial (NCT03069352) results in Blood¹ in which they assessed the safety and efficacy of combined RIC (venetoclax + low-dose cytarabine [LDAC]) for the treatment of AML. Interim results have previously been reported on the AML Hub here.

Study design

The study included adults with AML who were treatment-naïve but ineligible for intensive chemotherapy (due to age or comorbidities), randomized 2:1 to venetoclax plus LDAC or placebo plus LDAC. Patients were stratified by AML status (secondary or de novo), age, and region.

Venetoclax was administered a 100 mg on day 1, increasing to 600 mg by day 4 and continuing at 600 mg per day until day 28. Subsequent 28-day cycles were at the full 600 mg dose. LDAC was administered at 20 mg/m² per day on days 1–10. The venetoclax dose was adjusted if other inhibitors were used as part of the treatment regimen. The treatment continued until progression of disease, unacceptable toxicity, or consent was withdrawn.

Key findings

A total of 211 patients were included, with 210 patients receiving treatment (68 in the placebo arm, 143 in the venetoclax arm). The median duration of treatment was 3.9 months in the venetoclax arm (range, 1–17 months) and 1.7 months in the placebo arm (range, 0.1–14 months). The main reasons for discontinuation of treatment (venetoclax vs placebo) were treatment failure (12% vs 19%), progressive disease (11% vs 16%), death (12% for both), withdrawal of consent (6% vs 10%), adverse events not related to disease progression (9% for both), adverse events related to disease progression (4% for both), physician decision (5% vs 12%), morphologic relapse (13% vs 4%), and other (4% vs 3%).

In terms of safety, treatment emergent adverse events (TEAEs) are detailed in Table 1. Briefly, most TEAEs were hematologic in nature, as expected, and the most common TEAEs were thrombocytopenia and neutropenia. The most common non-hematologic TEAE was nausea, and the most common serious TEAE was febrile neutropenia. Each arm had a similar rate of TEAEs leading to death (23% vs 21%, venetoclax vs placebo), and similar 30-day mortality rates (13% vs 16%).

Table 1. Treatment emergent adverse events (TEAEs)

In terms of efficacy, at the planned primary analysis, the median follow-up time was 12 months in both arms, and 40% (57/143) and 31% (21/68) of the patients in the venetoclax and placebo arms, respectively, were alive. The primary outcome of median overall survival (OS) was 7.2 months (95%CI, 5.6–10.1) in the venetoclax arm vs 4.1 months (95% CI, 3.1–8.8) in the placebo arm. In a post-hoc analysis with another 6 months of follow-up, this increased to 8.4 vs 4.1 months. Upon analysis of baseline prognostic factors, AML status (de novo vs secondary), cytogenetic risk, Eastern Cooperative Oncology Group (ECOG) performance status, and age were significantly correlated with OS. CR or CRi was demonstrated in 48% (95% CI, 39–56) of patients in the venetoclax arm and 13% (95% CI, 6–24) in the placebo arm. CR alone was achieved in 27% and 7% (venetoclax vs placebo, respectively). The team also noted longer event-free survival (EFS) in the venetoclax arm vs the placebo arm (4.7 months vs 2.0 months).

Conclusion

The combination of venetoclax with LDAC was well tolerated, with a good safety profile and clinically meaningful benefits including OS, remission rate and EFS.  The accelerated induction of remission and positive benefit-risk profile suggest that venetoclax + LDAC may be an important treatment option for patients needing a RIC approach.