Azacitidine plus venetoclax as an alternative for hard-to-treat acute myeloid leukaemia patients

December 2020 Clinical practice Tobias Rawson

Acute myeloid leukaemia (AML) is a disease commonly associated with older age, with a median age of 68 at time of diagnosis. As a result, AML patients are often ineligible for the standard-of-care regimen of induction chemotherapy, allogeneic stem cell transplant and consolidation chemotherapy, due to incompatible comorbidities or simply because of advanced age. For these patients, the alternative is usually monotherapy with a hypomethylating agent, such as azacitidine, although this is associated with a remission rate of only 30% or less and a survival rate of less than 1 year. Within literature, B-cell lymphoma 2 (BCL2) proteins are known to be expressed on AML stem cells, and are dependent on BCL2 expression for survival. Furthermore, expression of BCL2 has been associated with a decreased responsiveness to chemotherapy and poor clinical outcome. Recently published in the New England Journal of Medicine, the phase III VIALE-A trial assessed the efficacy and safety of azacitidine, in combination with venetoclax, a BCL2 inhibitor, in newly diagnosed, treatment naive AML patients who were ineligible for the standard-of-care (SoC) regimen.

Study design

This phase III, randomised, double-blind, placebo-controlled trial randomised (2:1) 433 patients, to receive azacitidine 75mg/m2 on days 1-7 every 28-day cycle, plus venetoclax 400mg daily, or placebo until disease progression or unacceptable toxicity. Key eligibility criteria included an age of 18 or older, as well as a confirmed diagnosis of previously untreated AML that was ineligible for the standard-of-care regimen. Patients were ineligible for the SoC regimen if they were over 75, had a history of congestive heart failure or chronic stable angina, a diffuse carbon monoxide lung capacity of 65% or less, or a forced expiratory volume in 1 second of 65% of less, or an ECOG PS of ≥2. The primary endpoint in this study was overall survival (OS), with secondary endpoints of complete remission, composite complete remission, defined as complete remission or complete remission with incomplete haematological recovery, as well as safety.

Key findings

At a median follow-up of 20.5 months, the median overall survival (OS) of patients who received the azacitadine-venetoclax combination was 14.7 months, compared to 9.6 months in the control group (HR[95%CI]: 0.66[0.52-0.85], P< 0.001). Complete remission was also favourable to the study combination; 36.7% and 17.9%, respectively (P<0.001). Not surprisingly, the incidence of composite complete remission (cCR) followed a similar trend; 66.4% vs. 28.3%, respectively (P< 0.001). Interestingly, the cCR rate before initiation of cycle 2 was 43.4% and 7.6% for the combination and control arms (P< 0.001), with the median time to first response being 1.3 months and 2.8 months, respectively. The median duration of composite complete remission was also better in the azacitidine-venetoclax arm, compared to the control arm; 17.5 months vs. 13.4 months. The safety profile of azacitidine-venetoclax was consistent with the known side-effect profiles of both agents, and adverse events were consistent with expectations for an older AML population, and importantly, no differences in quality of life was observed between the two treatment arms.


In this study, patients treated with a combination of azacitidine plus venetoclax had a greater overall survival, with a response that lasted for a longer period of time, compared to azacitidine monotherapy. Importantly, this response came about quicker, observed in both time to response, as well as cCR rate before initiation of the second cycle of therapy. Ultimately, not only does this data prove the clinical efficacy of this combination in this setting, it also reveals a clinical benefit for the patient that allows them to live for longer, with a potentially greater quality of life.

AML in Belgium

In Belgium alone, as of 2012, approximately 2,000 new cases of myeloid malignancies are diagnosed every year, with AML accounting for 27% of these diagnoses. New, synergistic combination strategies, such as the ones investigated in this trial, enable better clinical outcomes to be implemented into clinical practice immediately, due to the currently availability of these therapeutics, ultimately giving patients better outcomes straight away.


DiNardo CD, et al., Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. New Eng J Med 2020; 383:617-629.

Factsheet on haematological malignancies by the Belgian Cancer Registry