Mechanisms of relapse and post-relapse outcomes following FLT3 inhibitor therapy in FLT3-mutated AML

A retrospective study assessed the cytomolecular mechanism of relapse and post-relapse outcomes in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) who received FLT3 inhibitor-containing regimens (N = 272). Findings were published by Arora et al. in the American Journal of Hematology. Patients received FLT3 inhibitors (FLT3i) including gilteritinib (39%), sorafenib (35%), quizartinib (20%), midostaurin (6%), and crenolanib (0.4%). 

Key data: After a median follow-up of 46 months, 80 patients (35% of responders) relapsed. FLT3 mutations were lost at relapse in 47% of patients. Patients who received intensive chemotherapy (IC) + FLT3i or hypomethylating agent (HMA) + venetoclax + FLT3i were more likely to show loss of an FLT3 mutation at relapse compared with those who received low-intensity therapy (LIT) + FLT3i without venetoclax (p = 0.05). Emergent non-FLT3 mutations were detected in 50% of relapsed patients, including DNA methylation mutations (21%), RAS pathway mutations (16%), and Wilms tumor 1 (WT1) mutations (13%). Median overall survival (OS) after relapse was 5.5 months.

Key learning: Loss of FLT3 mutations and emergence of non-FLT3 mutations represent common mechanisms of relapse following frontline FLT3i-based therapy in FLT3-mutated AML. Type of frontline regimen and transplantation influenced these patterns. Outcomes after relapse remain poor, highlighting the need for novel therapeutic strategies.