Acute promyelocytic leukemia (APL) has become a highly curable malignant disease after the introduction of all transretinoic acid (ATRA) to chemotherapy treatment. However, the risk to develop therapy-related myeloid neoplasms (t-MN) has become a matter of concern, as APL patients are otherwise expected to have a good prognosis. We report a patient with APL who achieved complete remission after chemotherapy induction with anthracycline and ATRA, followed by consolidation and maintenance chemotherapy. Two years later, the patient developed t-AML, with MLL rearrangements, without any evidence of relapse of the APL original clone. The increasing incidence of t-MN in oncohematological patients is partly due to the development of safer, more efficient or targeted therapies, which allow better outcomes and lengthened survival amongst treated patients. The identification of genetic factors, mechanisms or prognostic biomarkers in t-MN might open new windows for the development of personalized targeted therapy regimes in this underserved patient population.