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FLT3-ITD occurs in approximately 20%-25% of cases of adult AML and is associated with increased relapse risk and shorter survival. FLT3-ITD status informs AML risk at diagnosis, but its dynamic changes during disease evolution are not well defined. We hypothesized that divergent FLT3-ITD clonal trajectories are shaped by preexisting molecular features detectable at diagnosis. We analyzed 319 intensively treated adults who were newly diagnosed with non-M3 de novo AML who experienced relapse and had paired FLT3-ITD mutation data at diagnosis and relapse. Patients were classified into four clonal evolution patterns: maintained FLT3-ITD negative (FLT3-ITD^negative), FLT3-ITD loss (FLT3-ITD^lost), FLT3-ITD acquisition (FLT3-ITD^acquired), and maintained FLT3-ITD positive (FLT3-ITD^positive). The FLT3-ITD^positive group was strongly associated with concurrent NPM1 and/or DNMT3A mutations, which were enriched compared with those in other groups (p < 0.001). ELN 2022 risk categories differed across clonal evolution patterns, with favorable-risk disease declining progressively from the FLT3-ITD^negative to the FLT3-ITD^positive group (44.3%-6.1%) while intermediate-risk disease rose correspondingly (21.2%-73.5%; both p < 0.001). With a median follow-up of 96.8 months, patients in the FLT3-ITD^acquired or FLT3-ITD^positive group had significantly inferior relapse-free and overall survival compared with those in the FLT3-ITD^negative group (p = 0.009 and p = 0.018, respectively, in univariate analyses; p = 0.001 and p = 0.006, respectively, in multivariate analyses adjusted for individual genetic risk features). Transcriptomics showed enrichment of inflammatory pathways in FLT3-ITD^positive cases that persisted after adjustment for NPM1/DNMT3A co-mutations and FLT3-ITD allelic ratio, together with an inferred monocyte-rich profile. Overall, FLT3-ITD evolution is associated with distinct genomic and transcriptomic features present at diagnosis. TRIAL REGISTRATION: 202203013RSD.