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. Abbreviations 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...

Reduced-intensity allografting in patients with therapy-related myeloid neoplasms and active primary malignancies

“…1 Patients who require long-term immunosuppressive medication after solid organ transplantation also have a significantly increased risk of t-MNs. 2 According to the WHO classification, t-MNs constitute a separate disease entity comprising therapy-related (t) myelodysplastic syndrome (t-MDS), t-AML and myelodysplastic/ myeloproliferative neoplasms (t-MDS/MPN).…”

Therapy-related Leukemia with Inv(16)(p13.1q22) and Type D <i>CBFB/MYH11</i> Developing after Exposure to Irinotecan-containing Chemoradiotherapy

“…With the exception of irradiation and platinum-based agents (nedaplatin, cisplatin and carboplatin), which act basically as bifunctional alkylating agents to cause t-AML (1,20), the patient was treated with only irinotecan (total dose, 640 mg/ m 2 ) and docetaxel (total dose, 525 mg/m 2 ). Irinotecan is a semisynthetic derivative of camptothecin categorized as a topoisomerase I inhibitor (15).…”

Treatment related myeloid malignancies in childhood

“…Topoismerase inhibitors interfere with the enzymes involved in uncoiling the DNA in order to form single strands. This results in deletions, insertions, inversions and translocations [8]. Additional risk factors related to the use of medication are duration of exposure and cumulative dosage [47].…”

“…Examples of genetic predisposition are Down syndrome, Fanconi anemia, Li-Fraumeni syndrome, Leopard syndrome, Noonan syndrome and Costello syndrome. Several of them are related to RAS-MAPK pathways [8,[88][89][90][91][92][93][94]. The higher incidence of malignancies in relatives of patients with t-AML then in relatives of patients with de-novo AML and the occurrence of new malignancies in cancer patients treated with only surgery can be put forward for existence of yet unidentified factors [91].…”

“…An additional cause of t-AML is immune suppression; e.g., due to azathioprine [7]. Since most patients had combinations of inducing agents this WHO subclassification is currently not seen as relevant [8]. Generally both therapyrelated AML of secondary-AML terms are used.…”