Gilteritinib response in acute myeloid leukemia harboring a rare FLT3 juxtamembrane domain mutation with subsequent clonal evolution.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are among the most clinically relevant molecular abnormalities in acute myeloid leukemia (AML); however, the therapeutic significance of rare non-canonical FLT3 mutations involving the juxtamembrane domain (JMD) remains poorly defined. We report a 34-year-old woman with acute monocytic leukemia harboring a rare FLT3-JMD missense mutation (V579A) who experienced early relapse following standard induction and consolidation chemotherapy. Targeted next-generation sequencing revealed the presence of FLT3 V579A along with a concurrent truncating ARID1A mutation. Salvage therapy with the type I FLT3 inhibitor gilteritinib induced rapid hematologic remission within three weeks, allowing successful bridging to haploidentical allogeneic hematopoietic stem cell transplantation. Three months after transplantation, the patient relapsed, and genomic analysis demonstrated loss of the FLT3-mutated clone with the emergence and expansion of TP53-mutated independent clones, indicating clonal evolution and an apparent shift away from FLT3-dependent disease biology. This case suggests that AML harboring rare FLT3-JMD point mutations may exhibit transient dependence on FLT3 signaling and may respond to FLT3 inhibition despite the absence of canonical FLT3 alterations. These findings highlight the potential value of extended molecular profiling and longitudinal genomic assessment to identify potential therapeutic targets and mechanisms of resistance in relapsed AML.