Pretransplantation Hypomethylating Agents and Venetoclax in Acute Myeloid Leukemia Patients: A Real-World Analysis from the Cooperative Transplant Study Group

The combination of hypomethylating agents (HMA) and the BCL2 inhibitor venetoclax (VEN) has become standard first-line therapy for acute myeloid leukemia (AML) patients ineligible for intensive treatment and also is used as salvage therapy in relapsed/refractory (R/R) AML. Data on outcomes after subsequent allogeneic stem cell transplantation (allo-SCT) are limited. We retrospectively analyzed 91 patients with newly diagnosed (ND; n = 34) or R/R (n = 57) AML who received HMA/VEN followed by allo-SCT between 2020 and 2022. The overall response rate to HMA/VEN was 67%, with no significant difference between ND patients (73%) and R/R patients (64%). Pretransplantation measurable residual disease negativity was achieved in 49% of responders. Post-transplantation 2-year overall survival (OS) and relapse-free survival (RFS) were 52% and 42%, respectively, for the entire cohort, with similar outcomes for ND (2-year OS, 47%; RFS, 38%) and R/R (2-year OS, 56%; RFS, 45%) patients. In patients with high-risk features, such as TP53 mutation or complex karyotype (cKT), ND patients still achieved promising responses (TP53mut, 75%; cKT, 80%) and acceptable post-transplantation outcomes (2-year OS: TP53mut, 36%; cKT, 45%). In contrast, R/R patients showed lower response rates (TP53mut, 14%; cKT, 29%) and inferior outcomes (2-year OS: TP53mut, 29%; cKT, 29%). In conclusion, HMA/VEN is a feasible induction or salvage strategy enabling allo-SCT with encouraging outcomes in high-risk populations. In ND AML, this approach may expand transplant eligibility in older and frail patients; R/R patients with adverse molecular features may require alternative novel therapies or direct transplantation.