Therapy-Related Myeloid Neoplasms

Therapy-related myeloid neoplasms (t-MN) include AML (t-AML) and MDS (t-MDS) that arise secondary to cytotoxic chemotherapy and/or radiation therapy.[5] The therapy-related (or secondary) MDS are included because of their close clinicopathological relationships to therapy-related AML. Although these therapy-related disorders can be distinguished by the specific mutagenic agents involved, this distinction may be difficult to make because of the frequent overlapping use of multiple potentially mutagenic agents in treating cancer.[68] Because the associated cytogenetic abnormality, not the mutagenetic agent, determines prognosis and treatment it should be noted in the diagnosis.[10]

Since t-MN have been associated with germline pathogenic variants in cancer susceptibility genes, considering germline genetic testing or genetic counseling is warranted in those with strong family histories of cancer.[69]

Alkylating agent-related t-MN

The alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes typically occur 5 to 6 years after exposure to the mutagenic agent, with a reported range of approximately 10 to 192 months.[70,71] The risk of occurrence is related to both the total cumulative dose of the alkylating agent and the age of the patient.

Cytogenetic abnormalities have been observed in more than 90% of cases of t-MN and commonly include chromosomes 5 and/or 7.[70,72,73] Complex chromosomal abnormalities (≥3 distinct abnormalities) are the most common finding.[68,72-74]

Topoisomerase II inhibitor-related t-MN

Topoisomerase II inhibitor-related t-MN occurs in patients treated with topoisomerase II inhibitors. The agents implicated are the epipodophyllotoxins etoposide and teniposide and the anthracyclines doxorubicin and 4-epi-doxorubicin.[70] The mean latency period from the time of institution of the causative therapy to the development of t-MN is approximately 2 years.[75]

As with alkylating agent/radiation-related t-MN, the cytogenetic abnormalities are often complex.[68,72-74] The predominant cytogenetic finding involves chromosome 11q23 abnormalities and KMT2A pathogenic variants.[68,76]