AML-055 Outcomes Based on Sequential Use of Venetoclax Based Therapy and Targeted Therapy in Acute Myeloid Leukemia (AML)

Abstract

Treatment options for patients with AML have expanded with the approval of targeted therapies including FLT3 and IDH1/IDH2 inhibitors and venetoclax-based therapies. However, therapeutic efficacy based on alternate sequencing of these agents is not well described yet. In addition, little is known regarding molecular predictors of response to targeted therapy after venetoclax-based therapy and for the reverse sequence. The objective of this study was to describe the efficacy of targeted therapies following venetoclax-based therapy and contrast it with the efficacy of venetoclax post-targeted therapy in AML. In this multicenter, retrospective cohort study, we included 97 patients who received venetoclax-based therapy preceding (n=53) or following treatment with FLT3, IDH1 or IDH2 inhibitors (n=44) at 3 academic cancer centers in the United States. Response to therapy was determined using the 2017 European LeukemiaNet response criteria for AML The overall response rate (ORR) was defined as a composite of complete response (CR), CR with incomplete count recovery (CRi), partial remission (PR) and morphologic leukemia-free state (MLFS). Overall survival (OS) was calculated from the time of initiation of venetoclax, FLT3, IDH1, or IDH2 inhibitor therapies. Among patients treated with venetoclax after targeted agents, the ORR was 59.5% (CR: 19%) with a median OS of 9.2 months. Conversely, use of FLT3 (n=31), IDH1 (n=5) or IDH2 (n=17) inhibitors following venetoclax yielded an ORR of 17.7% and median OS of 4.2 months. Eight of 9 patients responding to targeted agents after venetoclax received gilteritinib. Univariate analysis demonstrated mutations in TP53 (hazard ratio [HR] for death: 44.99; 95% CI: 2.81 - 719.42; p<0.001) and KRAS (HR: 3.05; 95% CI: 1.05 - 8.86; p=0.035) to be associated with shorter OS in the targeted agent group, while FLT3-ITD mutations were associated with a shorter median OS (HR: 3.25; 95% CI: 1.55-6.79; p=0.002) in the venetoclax-treated cohort. Venetoclax can be an effective salvage therapy in patients previously treated with targeted therapy. However, while the FLT3 inhibitor gilteritinib retained clinical efficacy in patients previously treated with venetoclax, IDH1/2 inhibitors had very limited efficacy suggesting that alternative therapeutic strategies should be considered for these patients.