In patients receiving allogeneic hematopoietic cell transplantation to cure acute myeloid leukemia (AML), recurrence of the underlying disease, or relapse, represents a crucial unanswered issue and prominent cause of mortality. Still, over recent years, advancements in omic technologies have allowed us to gain new insights into the dynamic changes occurring in cancer and the host over the course of treatments, providing a novel evolutionary perspective on the issue of disease relapse. In this review, we summarize current knowledge on the molecular features of relapsing AML, with a specific focus on changes in the mutational asset of the disease and in the interplay between the tumor and the donor-derived immune system. In particular, we discuss how this information can be translated into relevant indications for monitoring transplanted patients and selecting the most appropriate therapeutic options to prevent and treat relapse.

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