Venetoclax plus azacitidine in young patients with AML

A higher-dose venetoclax plus azacitidine resulted in encouraging outcomes in young patients with newly diagnosed acute myeloid leukaemia (AML), supporting the hypothesis that the frontline therapy selection process should incorporate risk factors for chemotherapy outcomes and venetoclax outcomes instead of solely looking at fitness for chemotherapy.

“Risk factors for poor outcomes from intensive chemotherapy in patients with AML are established,” stated Dr Daniel Pollyea (University of Colorado, CO, USA) [1]. “For venetoclax-based therapies, corresponding risk factors are emerging.” Generally, patients with newly diagnosed AML will receive intensive induction chemotherapy if they are deemed fit for this treatment. However, Dr Pollyea hypothesised that risk factors should drive frontline therapy decisions over the ‘fitness for chemotherapy’ criterium. The current study enrolled patients between 18 and 59 years of age with previously untreated AML (excl. acute promyelocytic leukaemia) with adequate organ function, white blood cell counts ≤25,000x10⁹/L, and ELN intermediate or adverse risk. The 36 participants received azacitidine, 75 mg/m² on days 1–7, plus venetoclax, 600 mg/day on days 1–28. Participants without response after 1 cycle were excluded from the analysis; those who had a response but were MRD-positive received another cycle of the induction schedule; and those who were MRD-negative received maintenance therapy, comprising of azacitidine, 75 mg/m² on days 1–5, plus venetoclax, 400 mg/day on days 1–28.

Dr Pollyea mentioned that the response rate was 50% in the 8 participants with monocytic disease and 63% in the 19 participants without monocytic disease. Subsequently, previously unenrolled patients with monocytic disease could no longer participate in the study.

Thrombocytopenia (43%), neutropenia (28%), and anaemia (20%) were the most frequently observed adverse events of grade 3 or 4. “We also saw 2 early deaths that were not related to the study drugs, being a case of multi-organ failure and a case of respiratory failure,” added Dr Pollyea.

The overall response rate was 69%. Of the 25 participants with a response, 18 had a complete response, and 16 displayed MRD negativity. “Non-responders were able to receive salvage chemotherapy and increase their chance of transplant and survival,” said Dr Pollyea. After a median follow-up of 3.3 years, the median overall survival and duration of response were not reached.

The researchers also matched the first 28 enrolled participants to control subjects who had received intensive chemotherapy. There was a trend for a better response rate in participants on venetoclax plus azacitidine compared with those on intensive chemotherapy (61% vs 50%). Additionally, the median number of days spent in hospital was much lower in the venetoclax group than among chemotherapy receivers (7.5 vs 30.0; P<0.0001). “The infection rate was significantly higher in the chemotherapy group,” added Dr Pollyea (93% vs 39%; P=0.0071).

In conclusion, venetoclax plus azacitidine delivered promising results in young patients with newly diagnosed AML, challenging the traditional ‘frontline intensive chemotherapy’ paradigm in this population.

1. Watts J, et al. Venetoclax plus azacitidine for newly diagnosed younger acute myeloid leukemia patients independent of fitness for intensive chemotherapy. Abstract 969, 66^th ASH Annual Meeting, 7–10 December 2024, San Diego, CA, USA.

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Posted on 29 January 202529 January 2025