Therapy-related myeloid neoplasms: does knowing the origin help to guide treatment?

Abstract

Therapy-related myeloid neoplasms (t-MN) combine t-MDS and therapy related acute myeloid leukemia (t-AML) patients in one entity because of their similar pathogenesis, rapid progression from t-MDS to t-AML, and their equally poor prognosis. Treatment with epipodophyllotoxins like etoposide has been associated with a short interval between treatment and development of t-AML, with fusion oncogenes like KMT2A/MLL-MLLT3 and a better prognosis. In contrast, treatment with alkylating agents has been associated with a longer latency, an initial MDS phase, adverse cytogenetics, and a poor prognosis. The pathogenesis of t-MN can be explained by direct induction of an oncogene through chromosomal translocations, induction of genetic instability, or selection of a preexisting treatment-resistant hematopoietic stem cell clone. Recent evidence has highlighted the importance of the last mechanism and explains the high frequency of TP53 mutations in patients with t-MN. After previous cytotoxic therapy, patients present with specific vulnerabilities, especially evident from the high nonrelapse mortality in patients with t-MN after allogeneic hematopoietic cell transplantation. Here, the prognostic impact of currently known risk factors and the therapeutic options in different patient subgroups will be discussed.

Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer: a nationwide, observational follow up study in Sweden

“…The ICD codes used by the Swedish Cancer Registry do not specify treatment-related cancers, although the literature suggests that treatment-related cancers now account for 7% of acute myeloid leukaemia. 19 The study periods were constrained by the availability of data.…”

Therapy-related myeloid neoplasms as a concerning complication in acute promyelocytic leukemia

“… 5 , 7 It has been suggested that malignant cells with multiple aberrations are more immunogenic than cells with one or a few aberrations, and thus novel immune-based therapies, such as chimeric antigen-receptor T cells, bi-specific antibodies, and checkpoint inhibitors, should be considered in t-MN with a highrisk genetic profile and their evaluation in clinical trials should be encouraged. 4 Cytogenetic classification of t-AML should be further evaluated as a potential prognostic marker, and treatment recommendations should be based on performance status and karyotype. Recent unbiased approaches driven by gene expression analysis and Next Generation Sequencing have contributed to the identification of unique biomarkers associated with leukemia, which have the potential to significantly improve the diagnostic and prognostic criteria, and contribute to the continuous adaptation of treatment protocols.…”

“…Moreover, t-MN should be distinguished from AML with myelodysplasia (secondary AML), which is diagnosed either when 50% or more of the bone marrow cells are dysplastic in at least two lineages, when the patient had a previous diagnosis of MDS or MDS/MN or when myelodysplasia-associated cytogenetic aberrations are present. 3 , 4 …”

Genetic Pathway in the Pathogenesis of Therapy-Related Myeloid Neoplasms: A Literature Review

“…However, MMR does not remove the methylated base, and becomes a permanent mutation. This results in DSBs, leading to resistance to killing by methylating agents [ 7 , 17 , 21 , 23 ].…”

“…These inhibitors interfere with the re-ligation step during DNA replication and generate single-stranded DNA for the cancer cells. This mechanism reduces the progression and proliferation of cancer cells [ 17 , 19 ]. However, these inhibitors are not specific for cancer cells, and also cause DSBs of the normal cell DNA.…”