A number of environmental, occupational, and iatrogenic exposures have been identified that contribute to sAML via genotoxic damage to hematopoietic cells. Exposure to benzene, an organic component of many commonly used chemicals including plastics, dyes, pesticides, solvents, and petroleum products, has been linked to the subsequent development of AML. This relationship was identified in the 19th century, when bone marrow aplasia and myeloid leukemia were noted among workers exposed to benzene-containing chemicals. Individuals with occupational benzene exposure have an approximately threefold increased relative risk of developing AML. Workplace benzene exposures have decreased significantly since this discovery, but other sources of benzene exposure remain a concern (e.g., through cigarette smoking). Although cytopenias can occur within months of benzene exposure, there is a latency of several years between benzene exposure and the development of leukemia.
Cases of AML arising after chemotherapy or radiation have been historically designated as therapy-related AML (tAML). Two classes of chemotherapy drugs in particular are associated with an increased risk of tAML (Table 1); the first class of drugs with clear links to tAML are the topoisomerase II inhibitors. The most commonly used topoisomerase II inhibitors are anthracyclines, such as doxo rubicin, idarubicin, and daunorubicin, and the epipodophyllotoxin etoposide, which are critical components of many treatment regimens for both solid tumors and hematologic malignancies. Topoisomerase II is an adenosine triphosphate (ATP)-dependent enzyme that religates deoxyribonucleic acid (DNA) at sites of double-strand breaks to manage supercoils; inhibition of this enzyme increases the number of double-strand breaks. Resolution of these double-strand breaks may occur via error-prone nonhomologous end joining, resulting in accumulation of DNA damage or apoptotic cell death. tAML arising after exposure to topoisomerase II inhibitors typically occurs with a latency of 1 to 3 years and is often characterized by balanced chromosomal translocations, with the majority involving the KMT2A (mixed-lineage leukemia [MLL1]) locus on chromosome 11q23. Typical lesions are reciprocal translocations such as t(9;11)(p21;q23) and t(11;19) (q23;p13). Other rearrangements that occur in de novo AML also occur in tAML after topoisomerase II inhibitors, including t(15;17), t(8;21), and inv(16). The risk of tAML varies based on the chemo therapy dosing schedule, cumulative dose received, additional cytotoxic agents, and underlying disease characteristics but generally does not exceed 5% of patients treated with topoisomerase II inhibitors.
Table 1. Characteristic Features of Therapy-Related Acute Myeloid Leukemia
Alkylating agents are the second class of chemotherapy drugs with a clear role in the pathogenesis of tAML. The first leukemogenic agents identified in this category were nitrogen mustards. Frequently implicated drugs in contemporary clinical practice include cyclophosphamide, ifosfamide, and melphalan; weaker associations have been described with other alkylating agents such as busulfan, thiotepa, and cisplatin. Alkylating agents create adducts in DNA bases, which are variably mutagenic or cytotoxic. Cytogenetic lesions in alkylator associated tAML are typically unbalanced, including loss of the long arms of chromosomes 5 or 7 [del(5q), del(7q)], or complete loss of these chromosomes (−5, −7). The risk of tAML following alkylator exposure is up to 1% per year but typically has a longer latency (5 to 7 years) compared with topoisomerase II-associated tAML. The risk increases with age and cumulative exposure to these agents. In some cases of tAML, small clonal populations harboring TP53 mutations antedate chemotherapy exposure. TP53 deficiency may confer enhanced fitness on these clones, allowing them to expand under the selective pressure of therapy.
Several other therapies have also been implicated as risk factors for tAML, including some immunosuppressive therapies such as azathioprine, while other new associations continue to be investigated— for instance, possible tAML risk associated with poly (ADP-ribose) polymerase (PARP) inhibitors, particularly in patients with germline BRCA1/2 mutations.
Exposure to ionizing radiation also has been identified as a caus ative mechanism for tAML. This relationship was identified in the context of occupational exposures during the development of radiography and subsequently in the setting of mass exposures such as the atomic bomb detonations or nuclear power plant disasters, where a time-limited spike in leukemia incidence occurred following the event. Outside of these events, therapeutic radiation therapy represents the most common setting for significant radiation exposure, which is associated with a small but significant increase in tAML risk and likely varies depending on the site and dose of directed radiation therapy. Radiation-associated tAML is characterized by an increased frequency of mutations otherwise implicated in de novo AML pathogenesis—for instance, mutations in RUNX1, as well as balanced translocations such as RUNX1-RUNX1T1 and DEK-NUP214—suggesting some selectivity in the patterns of DNA damage.
