10-20% of all AML, MDS and MDS/MPN.
70% from solid tumor, 30% from hematological neoplasm; mostly breast CA and Hodgkin lymphoma.
Incidence increase with age; topoisomerase II inhibitor similar across all ages.
Heritable predisposition due to mutations in DNA repair, or gene polymorphism affecting drug metabolism/DNA repair.
- Cytotoxic therapy does not directly induce TP53 mutations but, rather, the presence of such mutations confers chemotherapy resistance to the mutant hematopoietic stem-progenitor cell clone permitting expansion at the expense of sensitive nonmutant HSPC.
- Preleukemic clonal hematopoiesis, comprising mutations in other genes such as TET2, DNMT3A, IDH2, and others, is common in patients with t-MDS/t-AML before exposure to chemotherapy or radiotherapy and may serve as a predictive marker to identify patients at risk of developing therapy-related myeloid malignancies.
- Common functional p53 pathway variants such as the MDM2 SNP309 and the TP53 codon 72 polymorphism may be associated with increased risk of developing t-AML.
Multilineage dysplasia, basophilia, reticulin fibrosis.
Monoblastic or myelomonocytic morphology.
Abnormal karyotype in > 90% of t-MN, 70% unbalanced abnormalities, 20-30% balanced translocations, 50% TP53.
5-year OS < 10%, median survival < 1 year.
Better prognosis in balanced translocation than unbalanced, but still worse than de novo counterparts.

Causes

Alkylating agents and ionizing radiotion
- 5-10 years of latent period
- Marrow failure
- Unbalanced loss of chromosome 5q/7/7q, complex karyotype, TP53
Topoisomerase II inhibitors
- 1-5 years of latent period
- Overt leukemia
- Balanced chromosomal translocation (11q23/KMT2A, 21q22.1/RUNX1)
Antimetabolites: fludarabine, MMF
Antitubulin agents
Hydroxyurea
L-asparaginase
Purine analogues

Prognosis