Pathogenesis

The development of acute myeloid leukemia (AML) or myelodysplastic neoplasms (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed therapy-related AML (t-AML) or therapy-related MDS (t-MDS). In addition to genotoxic exposures, genetic predisposition susceptibilities (such as polymorphisms in drug detoxification and DNA repair pathway components) may contribute to the occurrence of secondary AML/MDS.[1-4]

The risk of t-AML or t-MDS depends on the treatment regimen. It is often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered.[5] Regimens previously used that employed high cumulative doses of either epipodophyllotoxins (e.g., etoposide or teniposide) or alkylating agents (e.g., mechlorethamine, melphalan, busulfan, and cyclophosphamide) induced excessively high rates of t-AML or t-MDS that exceeded 10% in some cases.[5,6] However, most current chemotherapy regimens that are used to treat childhood cancers have a cumulative incidence of t-AML or t-MDS no greater than 1% to 2%.

t-AML or t-MDS resulting from exposures to epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of treatment and are commonly associated with chromosome 11q23 abnormalities.[7] Other subtypes of AML (e.g., acute promyelocytic leukemia) have also been reported.[8,9] t-AML that occurs after exposure to alkylating agents or ionizing radiation often presents 5 to 7 years later and is commonly associated with monosomies or deletions of chromosomes 5 and 7.[1,7]