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The clinical success of FLT3 inhibitors has led to their steadily increasing use in the treatment of acute myeloid leukemia (AML), both in the relapsed/refractory setting and as post-transplant maintenance. Despite their expanding application, there is currently no guidance on the optimal duration of therapy or the feasibility of discontinuation. In the maintenance context, current practice is largely based on trial protocols with predefined treatment periods, yet relapses after cessation have been documented. Similarly, in the relapsed/refractory setting, the management of long-term responders to FLT3-directed monotherapy lacks evidence-based guidance.We report two cases of FLT3-ITD AML patients with relapse after discontinuation of prolonged FLT3 inhibitor therapy, despite sustained remission prior to withdrawal. As such scenarios remain insufficiently characterized in the literature, these case vignettes are presented to highlight the unresolved challenge of defining the appropriate duration of FLT3 inhibitor therapy and to underscore the need for systematic evaluation to establish evidence-based strategies for safe discontinuation or extended administration.