Therapy-related myeloid neoplasms (t-MNs) are serious long-term consequences of cytotoxic treatments for an antecedent disorder. t-MNs are observed after ionizing radiation as well as conventional chemotherapy including alkylating agents, topoisomerase-II-inhibitors and antimetabolites. In addition, adjuvant use of recombinant human granulocyte-colony stimulating factor may also increase the risk of t-MNs. There is clinical and biological overlap between t-MNs and high-risk de novo myelodysplastic syndromes and acute myeloid leukaemia suggesting similar mechanisms of leukaemogenesis. Human studies and animal models point to a prominent role of genetic susceptibilty in the pathogenesis of t-MNs. Common genetic variants have been identified that modulate t-MN risk, and t-MNs have been observed in some cancer predisposition syndromes. In either case, establishing a leukaemic phenotype requires acquisition of somatic mutations -most likely induced by the cytotoxic treatment. Knowledge of the specific nature of the initiating exposure has allowed the identification of crucial pathogenetic mechanisms and for these to be modelled in vitro and in vivo. Prognosis of patients with t-MNs is dismal and at present, the only curative approach for the majority of these individuals is haematopoietic stem cell transplantation, which is characterized by high transplant-related mortality rates. Novel transplantation strategies using reduced intensity conditioning regimens as well as novel drugs -demethylating agents and targeted therapies -await clinical testing and may improve outcome. Ultimately, individual assessment of genetic risk factors may translate into tailored therapies and establish a strategy for reducing t-MN incidences without jeopardizing therapeutic success rates for the primary disorders.
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IntroductionTherapy-related myeloid neoplasms (t-MNs) are serious longterm consequences of chemo-and radiotherapy for an antecedent disorder. According to the World Health Organization (WHO) 'Classification of Tumours of Haematopoietic and Lymphoid Tissues', t-MNs comprise therapy-related myelodysplastic syndrome (t-MDS), acute myeloid leukaemia (t-AML) and myelodysplastic/myeloproliferative neoplasm, and constitute a unique clinical syndrome (Vardiman et al., 2009). They are observed after cytotoxic therapies of haematologic malignancies -mainly Hodgkin's disease (HD) and non-Hodgkin's lymphomas -as well as solid neoplasmsmost commonly breast, ovarian and prostate cancer. In addition, t-MNs have also been reported in patients receiving immunosuppressive treatment for rheumatologic/autoimmune diseases or solid organ transplantation (Offman et al., 2004;Kwong, 2010). The majority of patients with t-MNs present with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) transformed from MDS after a median latency period of 5-10 years following cytotoxic treatments with alkylating agents, immunosuppressive drugs or radiotherapy. Patients frequently exhibit marked peripheral blood cytopenias and dysplastic fe...