Therapy-related myeloid neoplasms: pathobiology and clinical characteristics

Abstract

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.

Figure 1

Similarities between therapy-related and high-risk de novo myeloid leukaemogenesis. In therapy-related myeloid neoplasms high doses of mutagenic chemo-/radiotherapy impact on the DNA of haematopoietic stem and precursor cells. In contrast, chronic exposure to low doses of occupational/environmental agents over extended periods of time may be operational in the development of high-risk de novo MDS/AML. Genetic variants conferring predisposition to the primary malignacy may also be of relevance for therapy-related leukaemogenesis and account for subtle biologic differences between t-MNs and high-risk de novo MDS/AML. MDS, myelodysplastic syndrome (MDS); AML, acute myeloid leukaemia.