Hypomethylating therapy plus venetoclax became standard for patients unfit for induction chemotherapy. PARADIGM asked the obvious next question: what happens if you give it to patients who are fit for induction?
This multicentre phase 2 trial randomised 172 previously untreated adults with acute myeloid leukaemia, all eligible for induction, 1:1 to azacitidine plus venetoclax or to induction chemotherapy. Median age was 64 years. Importantly, the trial excluded the groups where induction has the strongest case — core binding factor fusions, FLT3 mutations, and NPM1 mutations in patients under 60. Seventy-two per cent had adverse-risk disease by European LeukemiaNet 2022 criteria.
At a median follow-up of 21.9 months, median event-free survival was 14.5 months (95% CI 10.4 to 24.4) with azacitidine-venetoclax and 6.2 months (95% CI 4.1 to 10.1) with induction, hazard ratio 0.57 (95% CI 0.39 to 0.84, p=0.002). Toxicity favoured the same arm: grade 3 or higher infection in 28% versus 41%, and grade 3 or higher haemorrhage in 2% versus 12%.
The combination of better efficacy and less toxicity is what makes this hard to argue with, but the qualifications are substantial. This is phase 2, with 172 patients, and event-free survival is not overall survival — a longer time to relapse does not automatically mean more people cured, and in a disease where cure depends on transplant the relevant question is who reaches transplant in remission.
Where it lands hardest is in settings where induction's supportive care burden is the binding constraint. In Indian practice, four weeks of profound neutropenia with reliable blood product support and antifungal cover is not available everywhere; an outpatient-deliverable regimen with a third less severe infection changes who can be treated at all.
- Consider azacitidine-venetoclax as a genuine alternative in induction-eligible patients with adverse-risk disease, not only in the unfit
- Note the exclusions: core binding factor fusions, FLT3 mutations, and NPM1 mutations under 60 were not studied and induction remains standard there
- Weigh the toxicity difference explicitly — a third less grade 3 infection and a six-fold reduction in serious bleeding
- Do not read event-free survival as cure; plan the transplant pathway from the outset
- Where supportive care capacity limits who can receive induction, this regimen widens who can be treated
The statistics, in plain English
A hazard ratio of 0.57 with an interval of 0.39 to 0.84 excludes no effect, and the median difference of over eight months is large. Two cautions temper it. First, this is phase 2 with 172 patients, so it is designed to justify a phase 3 trial rather than to settle practice, and phase 2 effect sizes in oncology are systematically larger than what phase 3 confirms. Second, event-free survival counts induction failure, relapse and death together, and a regimen that produces fewer early treatment failures will look good on this endpoint even if long-term survival is unchanged. Overall survival is the number to wait for.
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