Comparative effectiveness of HMA with venetoclax vs intensive chemotherapy in AML with very high-risk cytogenetics

The optimal frontline therapy for acute myeloid leukemia (AML) with very high-risk cytogenetics (vHRC)-defined by complex karyotype (CK), monosomal karyotype (MK), or inv(3)/t(3;3)-remains uncertain. We retrospectively analyzed 358 newly diagnosed AML-vHRC cases treated at five academic centers (2014-2024), stratified by intensive chemotherapy (IC) vs hypomethylating agent plus venetoclax (HMA+ven). Cytogenetic features included CK in 90.2%, MK in 64%, and inv(3)/t(3;3) in 9.8%; TP53 mutations occurred in 51%. Frontline therapy was IC in 40% and HMA+ven in 60%, with a median age of 67 years (range, 22-92). Median overall survival (OS) for AML-vHRC was 8 months compared with 31 months for non-vHRC AML (P < .0001). Composite complete remission (cCR) rates were similar with IC vs HMA+ven (55% vs 54%, P = .91). Patients with inv(3)/t(3;3) had inferior responses (cCR 36%) compared with CK/MK-AML (67%; P < .001). No OS differences by frontline regimen were observed among patients aged 60-75 years (7.7 vs 6.6 months, P = 0.43), those with TP53-mutated disease (8.1 vs 5.8 months, P = .17), or following allogeneic hematopoietic stem cell transplantation (alloHSCT; 35 vs 25 months, P = .56). On multivariable analysis, older age (HR 1.02, P = .0003), inv(3)/t(3;3) (HR 2.12, P = .0002), and TP53mt (HR 2.07, P < .0001) independently predicted inferior OS, whereas alloHSCT improved OS (HR 0.42, P < .0001); frontline regimen (HMA+ven vs IC) was not associated with OS (HR 0.84, P = .2814). In AML-vHRC, IC and HMA+ven yield comparable remission and survival outcomes. Given equivalent efficacy and similar early mortality, HMA+ven represents a reasonable frontline option for patients aged 60-75 years, those with TP53mt disease, and patients intended for alloHSCT.