Therapy-related myeloid
neoplasms (t-MN) include
acute myeloid leukemias and
myelodysplastic syndromes arising in patients who have been treated with
chemotherapy,
radiation therapy,
immunosuppressive agents or after documented exposure to environmental
carcinogen. t-MN are defined according to the primary treatment and the corresponding genetic and molecular lesions. Chromosome(s) 7 and/or 5
monosomies or deletions are typical of
alkylating agent-induced AML, while balanced translocations involving chromosome bands 11q23 and 21q22 are associated to preceeding
therapy with
DNA-topoisomerase II inhibitors.
Antimetabolites, and in particular the
immunosuppressive agents azathioprine and
fludarabine, have also been recently associated to t-MN.
Leukemias developing after
benzene exposure are similar to t-MN and are characterized by
chromosomal aberrations, which have been also observed among otherwise healthy
benzene-exposed workers. Individual predisposing factors, including polymorphisms of detoxification and
DNA-repair enzymes have been identified. Two genetic variants in key metabolizing
enzymes,
myeloperoxidase and
NAD(P)H:
quinone oxidoreductase, have been shown to influence susceptibility to
benzene hematotoxicity. Combination of polymorphisms impairing detoxification and DNA repair may significantly increase
therapy-related myeloid
neoplasm risk. Among
hematological malignancies, long-term survivors of
Hodgkin's lymphoma are exposed to an increased t-MN risk, particularly when receiving MOPP-based and escalated-BEACOPP regimens, and when
alkylators are combined to
radiotherapy. Patients with
lymphoma are at highest risk if total body irradiation followed by autologous
stem cell transplantation is used as rescue or consolidation. The addition of
granulocyte-colony stimulating factor (
G-CSF) and
radiotherapy plays a significant role in t-MN following treatment of childhood
acute lymphoblastic leukemia. In solid
tumors, treatment for
breast cancer and
germ-cell tumors has been associated with a 1-5% lifetime risk of t-MN.