Divergent Clonal Trajectories of FLT3 ‐ITD in Acute Myeloid Leukemia and Their Clinical and Transcriptomic Associations

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