- Design
- Multicentre, randomised phase 2 trial
- Population
- 172 induction-eligible adults with untreated AML; 72% adverse risk
- Primary outcome
- Event-free survival
- Effect
- 14.5 vs 6.2 months; HR 0.57 (95% CI 0.39 to 0.84)
PARADIGM was a multicentre phase 2 trial that randomised 172 previously untreated adults with AML who were eligible for intensive induction to azacitidine plus venetoclax or induction chemotherapy. Patients with core-binding-factor fusions, FLT3 mutations, or NPM1 mutations under age 60 were excluded. Median age was 64 and 72% had adverse-risk disease by ELN 2022. It was published in NEJM in September and funded partly by the venetoclax manufacturer.
At median follow-up of 21.9 months, event-free survival was 14.5 months with azacitidine-venetoclax and 6.2 months with induction (HR 0.57, 95% CI 0.39 to 0.84). Grade 3 or worse infection occurred in 28% versus 41%, and grade 3 or worse haemorrhage in 2% versus 12%.
For fit patients with adverse-risk AML, where intensive induction performs poorly, this challenges the assumption that intensity is the route to cure. It is a phase 2 trial with event-free survival rather than overall survival as the primary end point, so it supports discussion and trial enrolment rather than a wholesale switch.
- Classify risk and mutations (FLT3, NPM1, core-binding factor) before choosing induction.
- Discuss azacitidine-venetoclax as an option for fit adults with adverse-risk AML, ideally within a trial.
- Keep intensive induction for favourable-risk and FLT3- or NPM1-driven disease.
- Plan transplant assessment regardless of induction choice.
Why it matters
It questions whether intensive induction is the best first step for fit patients with adverse-risk disease.
Don't overread it
A phase 2 trial with event-free survival as its end point has not shown longer overall survival.
The statistics, in plain English
An HR of 0.57 means events occurred at about 57% of the rate with induction, and the interval stays below 1. With 86 patients per arm, estimates are imprecise. Event-free survival counts failure to reach remission as an event, which can favour a regimen with more gradual responses; overall survival is not reported in the abstract.
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