Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML

Although intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% 95% confidence interval (CI), 52-69% vs 38% 95% CI, 27-55%; P = .013), it was not statistically different among patients aged 60-75 years (60% 95% CI, 52-70% vs 44% 95% CI, 29-66%; P = .069) and patients who received an allogeneic stem cell transplant (70% 95% CI, 58-85% vs 66% 95% CI, 44-100%; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% 95% CI, 56-74% with IC vs 40% 95% CI, 26-60% with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% 95% CI, 59-79% vs 43% 95% CI, 29-63%; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25).