Background: Venetoclax in combination with hypomethylating agents (HMA+Ven) is the standard-of-care treatment for patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. HMA+Ven is also commonly used as salvage therapy for relapsed or refractory (R/R) AML. There is limited data regarding outcomes of AML patients after HMA+Ven failure. In clinical practice, survival following HMA+Ven failure, either as frontline or salvage therapy, is observed to be poor. Methods: We conducted a single center retrospective study to evaluate survival outcomes of AML patients who were R/R to HMA+Ven as frontline or salvage therapy. Patients ≥ 18 years of age with AML who initiated HMA+Ven between 06/2018 and 05/2021 were included. R/R AML was defined as clinically relevant disease with ≥ 5% blasts after prior complete remission/morphologic leukemia free state, refractoriness to at least two cycles of HMA+Ven, or progressive disease despite initiating HMA+Ven. Data cut-off was 02/07/2022. Overall survival (OS) was estimated using Kaplan-Meier method and outcome differences between sub-groups were assessed using the log rank test. Results: Forty-two patients met inclusion criteria. Baseline characteristics and treatment details are summarized in Table. The median OS of the overall cohort was 2.3 months (range 0.1-11.4). There was no significant difference in median OS between patients declared R/R to frontline vs salvage HMA+Ven (2.4 vs 1.8 months, hazard ratio [HR] = 0.84, 95% confidence interval [CI] 0.43-1.62). Patients who received treatment after HMA+Ven failure had longer median OS compared to patients who did not (n = 17, 4.7 vs 1.7 months, HR = 0.29, 95% CI 0.13-0.62). There was no significant difference in OS based on the sub-type of AML, ELN risk group, p53 mutation, or complex karyotype status. Conclusions: Data from our study support the clinical observation that AML patients with disease R/R to HMA+Ven, either as frontline or salvage therapy, have very poor survival outcomes. These results provide important prognostic information for clinicians and highlight the need for novel therapies for R/R AML.

AML: acute myeloid leukemia; ELN: European LeukemiaNet; HMA: Hypomethylating agent; Ven: venetoclax.