Intensive chemotherapy versus venetoclax–hypomethylating agents therapy for acute myeloid leukemia: A large real-world propensity-matched study.

e18541 Background: Intensive induction chemotherapy (IC) with cytarabine and an anthracycline has been the frontline approach for acute myeloid leukemia in fit adults for decades. Despite its long use, long-term survival remains limited, and it has significant toxicities. In VIALE-A, venetoclax with azacitidine (Ven-Aza) improved survival and remission rates among patients who were not candidates for IC. The phase 2 PARADIGM trial compared Ven-Aza with standard IC in fit adults and reported higher response rates and better event-free survival with Ven-Aza. Using a large, real-world cohort with propensity-matched controls, we compared survival outcomes between patients treated with IC and those treated with Venetoclax combined with a hypomethylating agent (Ven-HMA). Methods: Using the TriNetX research network, adults with AML receiving either IC or Ven-HMA as initial therapy were identified; patients with acute promyelocytic leukemia were excluded. Cohorts were propensity score–matched 1:1 on age, sex, comorbidities, TP53 mutation, and the presence of another primary malignant neoplasm. The primary outcomes were mortality at 3, 6, and 12 months. Secondary outcomes included sepsis, acute kidney injury (AKI), tumor lysis syndrome (TLS), and acute myocardial infarction (AMI) or stroke. Results: After matching, 2,588 patients were included per cohort. At 3 months, mortality was lower with IC than with Ven-HMA 13.7% versus 18.1% (hazard ratio HR 0.75, 95% CI 0.65–0.86; log-rank p<0.0001). At 6 months, mortality remained lower with IC, 20.3% versus 29.6% (HR 0.66, 95% CI 0.59–0.74; log-rank p<0.0001), and at twelve months, 30.8% versus 44.9% (HR 0.63, 95% CI 0.58–0.69; log-rank p<0.0001), favoring IC across all intervals. Incidents of sepsis (35.2% vs 32.5%; p = 0.047) and AKI (40.7% vs 37.9%; p = 0.04) were modestly higher with IC, whereas TLS and stroke or AMI were similar between groups. Conclusions: IC was associated with significantly improved short-term survival compared with Ven-HMA therapy among patients with AML, despite slightly higher risks of sepsis and acute kidney injury. These findings suggest that while Ven-HMA remains an appropriate option for patients unfit for intensive therapy, IC continues to provide superior survival outcomes in appropriately selected patients. Further studies integrating molecular risk stratification and measurable residual disease are warranted to optimize treatment selection in AML.