Epigenetic changes in therapy-related MDS/AML

The purpose of this review is to update knowledge on therapy-related myeloid neoplasms (t-MNs), taken into account the new 2008 WHO classification, new genome-wide approaches for the definition of susceptibility towards t-MN and the introduction of new more aggressive treatments in cancer patients. Recent findings t-MNs are an increasing matter in cancer survivors treated with chemoradiotherapy. One of the major concerns in hematologic malignancies is childhood acute lymphoblastic leukemia (ALL), in which the leukemogenic role of extended etoposide/teniposide treatment, concomitant intensive antimetabolite and asparaginase, granulocyte colonystimulating factor (G-CSF) and prophylactic cranial radiotherapy use have been established. In high-risk Hodgkin lymphoma, 3% t-MNs have been observed at 10-year follow-up with the escalated BEACOPP schedule, versus 0.4% with ABVD. In lymphoproliferative diseases the new drugs fludarabine and lenalidomide may increase the risk of second tumors, when associated to other cytotoxic therapies. Among solid tumors, breast cancer is most frequently associated to t-MN. The risk is correlated to higher chemotherapy doses, radiotherapy, use of G-CSF, but also independent from treatment, suggesting a genetic predisposition to both diseases. Radiotherapy plays a role also in female pelvic tumors and in testicular cancer, when associated to cisplatin. Summary The risk of t-MN is not negligible, although below 2% in most series. This is particularly significant for younger cancer patients and during the first 5 years after the primary malignancies. Efforts should be maximized to identify susceptibility factors to identify patients at risk, in whom more leukemogenic drugs and schedules should be avoided.