Outcome of patients with acute myeloid leukemia following failure of frontline venetoclax plus hypomethylating agent therapy

Outcome of patients with acute myeloid leukemia following failure of frontline venetoclax plus hypomethylating agent therapyVenetoclax (Ven) in combination with hypomethylating agents (HMA) is Food and Drug Administration-approved for elderly/unfit acute myeloid leukemia (AML) patients.In the phase III VIALE-A study, complete remission (CR) with or without count recovery (CRi) was achieved in 66.4% of previously untreated patients with AML receiving Ven and azacitidine.CR/CRi was superior in the presence of IDH1/2, NPM1, FLT3, and TP53 mutations in the Ven and azacitidine arm compared to treatment with azacitidine alone. 1However, disease progression or relapse was documented in 42% of patients on Ven and azacitidine therapy. 1 Similarly, in a separate study of 95 newly diagnosed AML patients treated on frontline Ven+HMA clinical trials, 41 (43%) of patients experienced relapsed or refractory disease; median overall survival after Ven+HMA failure was considerably inferior at 2.4 months, particularly in patients that did not receive salvage therapy (1.3 months). 2 On the other hand, outcomes of AML patients following failure of upfront Ven+HMA therapy outside the context of clinical trials have not been well-studied.Accordingly, in the current study, our primary objective was to describe the clinical outcomes of patients with AML following failure of frontline Ven+HMA therapy in routine clinical practice and identify clinical and molecular predictors of survival after Ven+HMA failure.Patients with newly diagnosed AML treated with frontline Ven+HMA outside clinical trials at the Mayo Clinic between 2018 and 2020 were retrospectively recruited after Institutional Review Board approval.Follow-up was updated in November 2022.All patients received at least one cycle of either azacitidine 75 mg/m 2 days 1-7 or decitabine 20 mg/m 2 days 1-5 with Ven dose-adjusted based on azole antifungal prophylaxis. 3Bone marrow biopsy was obtained after either cycle 1 or 2 based on treating physician discretion with response assessed according to the 2017 European Leukemia Net (ELN) criteria. 4Treatment failure was defined as inability to achieve CR/CRi (refractory) or loss of CR/CRi (relapsed).Cytogenetic and molecular studies were performed at the time of AML diagnosis by conventional karyotype, and next-generation sequencing (42-gene panel), respectively in all patients, while a subset of patients underwent molecular testing at the time of relapsed/refractory disease.Survival was calculated from the time of treatment initiation and from onset of relapsed or refractory disease to last follow-up or death and survival curves prepared by the Kaplan-Meier method and compared by the log-rank test.Cox proportional hazard model was used for multivariable analysis.JMP Pro 16.0.0software package, SAS Institute, Cary, NC was used for statistical analysis.