Azacitidine–venetoclax challenges induction chemotherapy in fit AML

Design

Multicentre, randomised, phase 2 trial (PARADIGM)

Population

172 induction-eligible adults with untreated AML (favourable-risk excluded)

Primary outcome

Event-free survival

Effect

Median EFS 14.5 vs 6.2 months, hazard ratio 0.57 (95% CI 0.39–0.84)

Induction chemotherapy has been the standard for fit patients with acute myeloid leukaemia for decades, despite its toxicity. PARADIGM, a phase 2 trial, randomised 172 previously untreated adults who were eligible for induction to azacitidine plus venetoclax — the chemotherapy-free regimen usually reserved for unfit patients — or to standard induction. Favourable-risk disease (core-binding-factor, and FLT3 or NPM1 mutations under 60) was excluded; median age was 64 and 72% had adverse-risk disease.

Event-free survival was longer with azacitidine–venetoclax: median 14.5 versus 6.2 months (hazard ratio 0.57, 95% CI 0.39–0.84). Serious infection (28% vs 41%) and major bleeding (2% vs 12%) were less frequent than with induction.

This is a phase 2 signal in a selected, largely adverse-risk group, with event-free rather than overall survival as the endpoint — so it reopens the question of whether fit patients need intensive induction, rather than settling it. For an Indian setting where induction's infection risk and intensive-care demands are a real constraint, a less toxic oral-and-injectable regimen is an attractive hypothesis to test further.

• In fit AML, azacitidine–venetoclax gave longer event-free survival than induction chemotherapy (14.5 vs 6.2 months).
• Serious infections and major bleeding were less frequent than with induction.
• Favourable-risk subtypes were excluded, and most patients had adverse-risk disease.
• The endpoint was event-free, not overall, survival, in a phase 2 trial.

Why it matters

It questions whether fit AML patients still need intensive induction chemotherapy, a long-held assumption.

Don't overread it

A phase 2 trial of 172 selected patients, reporting event-free rather than overall survival — hypothesis-strengthening, not practice-settling.

The statistics, in plain English

A hazard ratio of 0.57 is a large relative gain and the interval stays below 1.0, but event-free survival can improve without overall survival following, and the modest sample leaves the estimate imprecise.

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