Cancer treatment may also cause secondary malignant neoplasms. Which agent has been linked to later development of Acute Myeloid Leukemia (AML) and myelodysplastic syndrome (MDS)?

• A. Ifosfamide
• B. Corticosteroids
• C. Cyclophosphamide
• D. Etoposide

Answer: (D)

Therapy-related leukemias are a known late complication of certain chemotherapy drugs. Etoposide is a topoisomerase II inhibitor; it can cause DNA double-strand breaks. If these breaks are misrepaired, they create chromosomal rearrangements, commonly involving the 11q23/MLL region, which are characteristic findings in therapy-related AML and, less often, in myelodysplastic syndrome. Because of this mechanism, exposure to etoposide has been linked to developing AML/MDS years after treatment, typically within a shorter latency window than some other agents. While alkylating agents like cyclophosphamide or ifosfamide can also lead to therapy-related AML/MDS, they usually do so after a longer period and with different cytogenetic patterns. So, etoposide best fits the described association.