- Design
- multicentre, randomised phase 2 trial, 1:1, median follow-up 21.9 months (PARADIGM)
- Population
- 172 previously untreated adults with AML eligible for induction chemotherapy; median age 64, 72% adverse-risk; core binding factor, FLT3-mutant and younger NPM1-mutant disease excluded
- Primary outcome
- event-free survival
- Effect
- median 14.5 months (95% CI 10.4-24.4) vs 6.2 months (95% CI 4.1-10.1); hazard ratio 0.57 (95% CI 0.39-0.84), P=0.002
Hypomethylating therapy with venetoclax became standard for adults with acute myeloid leukaemia who cannot tolerate induction chemotherapy. PARADIGM asked the harder question: what happens in patients who can. It randomised 172 previously untreated adults eligible for induction chemotherapy, 1:1, to azacitidine plus venetoclax or to induction chemotherapy. Median age was 64 and 72% had adverse-risk disease by the European LeukemiaNet 2022 classification. Patients with core binding factor fusions, FLT3 mutations, or NPM1 mutations under the age of 60 were excluded.
At a median 21.9 months, median event-free survival was 14.5 months (95% CI 10.4 to 24.4) with azacitidine-venetoclax against 6.2 months (95% CI 4.1 to 10.1) with induction chemotherapy, hazard ratio 0.57 (95% CI 0.39 to 0.84), P=0.002. Serious toxicity ran the same way: grade 3 or higher infection in 28% against 41%, and grade 3 or higher haemorrhage in 2% against 12%.
The reason this reaches a general readership is that induction chemotherapy is one of the most demanding treatments in medicine, requiring weeks of inpatient care, transfusion support and neutropenic management, and any clinician who admits or shares care for these patients feels its consequences. A better-tolerated oral and injectable regimen with longer event-free survival changes what those months look like.
Read the exclusions before generalising. The genetic groups left out, core binding factor and FLT3 and younger NPM1-mutant disease, are precisely those in which induction chemotherapy performs best, so this trial deliberately tested the comparison where induction was least favoured. It is also a phase 2 trial of 172 patients reporting event-free rather than overall survival, so it is a strong signal for a phase 3 answer rather than the answer itself.
- Do not extend this to core binding factor, FLT3-mutant or younger NPM1-mutant AML, which were excluded
- Note the endpoint is event-free survival at a median 21.9 months, not overall survival
- Expect fewer severe infections and much less serious bleeding with the azacitidine-venetoclax regimen
- Confirm the genetic and cytogenetic panel before any first-line decision in AML; it determines which trial applies
- Treat this as a phase 2 result that should change referral discussions, not local protocol, until phase 3 data arrive
The statistics, in plain English
A hazard ratio of 0.57 with an interval from 0.39 to 0.84 means the rate of events or death was around 43% lower and chance is an unlikely explanation, but the interval is wide, spanning a 16% to 61% reduction, which is what 172 patients buys. Event-free survival counts treatment failure, relapse and death together, so it responds faster than overall survival and can improve without lives being extended; whether that follows here is not yet known. The confidence intervals on the two medians overlap at their edges (10.4 to 24.4 against 4.1 to 10.1), which is common and does not contradict the significant hazard ratio, since the hazard ratio uses the whole survival curve rather than a single point on it.
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