Therapy-related leukemia and myelodysplasia: susceptibility and incidence

Abstract

Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is an increasingly recognized treatment complication in patients treated with radiotherapy or chemotherapy for previous hematologic malignancies or solid tumors. Distinct clinical entities have been described according to the primary treatment, corresponding to defined genetic lesions. Chromosome 7 and/or 5 losses or deletions are typical of alkylating agent-induced AML, while development of t-AML with balanced translocations involving chromosome bands 11q23 and 21q22 has been related to previous therapy with drugs targeting DNA-topoisomerase II. In addition, anti-metabolites, and in particular the immunosuppressant azathioprine, have been shown to induce defective DNA-mismatch repair. This could promote survival of misrepaired cells giving rise to the leukemic clone. Individual predisposing factors, including polymorphisms in detoxification and DNA repair enzymes have been identified. Their combination may significantly increase the risk of t-MDS/AML. Among patients with hematologic malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased risk of t-MDS/AML, particularly when receiving MOPP-based, and escalated BEACOPP regimens, and when alkylators are combined with radiotherapy. Patients with Hodgkin's and non-Hodgkin's lymphoma are at highest risk when total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation therapy. The addition of granulocyte-colony-stimulating factor and radiotherapy plays a significant role in t-AML following treatment of children with acute lymphoblastic leukemia. In non-hematologic malignancies, treatment for breast cancer and germcell tumors has been associated with a 1-5% lifetime risk of both lymphoid as well as myeloid leukemia. In all cases the risk of t-MDS/AML drops sharply by 10 years after treatment.Key words: susceptibility, therapy-related, AML, MDS. Established genetic factors alone explain approximately 5% of all cancers, the remainder can be attributed to environmental carcinogens, tobacco smoke, dietary costituents, pollutants, drugs, radiation, and infectious agents that act in conjunction with both genetic and acquired susceptibility.1 Yet, the role of exogenous factors is not always so evident. Apart from radiotherapy and chemotherapy, which are recognized as the most frequent causes of secondary malignant neoplasms, therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndromes (t-MDS) account for 10-20% of all cases of AML.2 In the GIMEMA registry, the incidence of AML occurring as a second malignancy was about 5%, but this registry includes only patients in whom treatment is feasible.3 The high incidence of t-AML has been attributed to the increasing use of cytotoxic drugs causing DNA damage, and to the longer survival of many treated patients. Yet, only a minimal proportion of subjects exposed present with a secondary leukemia, indicating that an important role is played by the susceptibility of hemato...

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

“…Irrespective of these details, our data suggest the intriguing possibility to kill malignant myeloblast by inhibiting (one of) the upstream kinase(s) that account for constitutive activation of the NF-kB pathway. Although other studies suggested that ATM might be used as a chemo-or radiosensitizing agents (Leone et al, 2007), the result of our work implies that ATM inhibition as such could have a therapeutic effect on high-risk MDS and AML. This hypothesis warrants further preclinical and clinical exploration.…”

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

“…13,80 MDS/AML risk after allogeneic HCT is thought to be comparable to that of other cancer survivors who have received particular cytotoxic chemotherapeutic agents and radiotherapy, with such risks often exceeding 10-fold. 81 There is also some evidence that MDS/AML risks may be even higher after autologous HCT because of the substantial cumulative doses received during pre-transplant chemotherapy and radiotherapy, chemotherapy-based stem cell mobilization and HCT conditioning. 62,82,83 …”

Chronic Myeloid Leukemia Developing After Successful Treatment of Acute Promyelocytic Leukemia

“…Patients usually developed t-MDS or t-AML with a latency ranging from 22 to 46 months after receiving chemotherapy [3]. Cytogenetic abnormalities such as losses or deletions of chromosome 7 and/or 5 and recurrent balanced translocations involving 11q23 and 21q22 are frequently observed in t-AML and t-MDS, and are regarded as important hallmarks for the diagnosis of these two entities [4]. Our patient demonstrated unusual clinical features.…”