The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Blood (Impact Factor: 10.43). 02/2011; 117(7):2137-45. DOI: 10.1182/blood-2010-08-301713
Source: PubMed

ABSTRACT To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

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    • "Therapy-related acute myeloid leukemia (t- AML) is becoming an increasingly important late effect following treatment for a primary malignancy due to increased survival rates in patients. At present, about 10% of all AML cases arise after exposure to chemotherapy and/or radiation for a primary malignancy or autoimmune disease (Kayser et al., 2011). Topoisomerase II (TOP2) poisons are used in many chemotherapy treatment protocols and consist of intercalating agents, such as mitoxantrone, and non-intercalating agents, such as etoposide (Cowell and Austin, 2012). "
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    ABSTRACT: Rearrangements involving the RUNX1 gene account for approximately 15% of balanced translocations in therapy-related acute myeloid leukemia (t-AML) patients and are one of the most common genetic abnormalities observed in t-AML. Drugs targeting the topoisomerase II (TOP2) enzyme are implicated in t-AML; however, the mechanism is not well understood and to date a single RUNX1-RUNX1T1 t-AML breakpoint junction sequence has been published. Here we report an additional five breakpoint junction sequences from t-AML patients with the RUNX1- RUNX1T1 translocation. Using a leukemia cell line model, we show that TOP2 beta (TOP2B) is required for induction of RUNX1 chromosomal breaks by the TOP2 poison etoposide and that, while TOP2 alpha (TOP2A) and TOP2B proteins are both present on RUNX1 and RUNX1T1 chromatin, only the TOP2B enrichment reached significance following etoposide exposure at a region on RUNX1 where translocations occur. Furthermore, we demonstrate that TOP2B influences the separation between RUNX1 and two translocation partners (RUNX1T1 and EVI) in the nucleus of lymphoid cells. Specifically, we identified a TOP2B-dependent increase in the number of nuclei displaying juxtaposed RUNX1 and RUNX1T1 loci following etoposide treatment. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 02/2014; 53(2):117-28. DOI:10.1002/gcc.22124 · 3.84 Impact Factor
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    • "In one report , median age of t-AML was 57.8 years versus 53.2 years in de novo AML. (Kayser et al., 2011) While the above factors contribute to the worse outcome seen in t-AML, inferior survival and response rate has been observed in all age and cytogenetic subgroups (Grimwade & Hill 2009; Borthakur et al., 2009), See figure 7. Fig. 7. Survival curves according to cytogenetics subgroups for patients treated in MRC AML trials (AML10, 11, 12, 14 and 15) with t-AML and de novo AML (Grimwade & Hill 2009). "
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    ABSTRACT: Breast cancer is the most frequent cancer among women and the leading cause of death among middle-aged women. Early detection by mammography screening and improvement of therapeutic options have increased breast cancer survival rates, with the consequence that late side effects of cancer treatment become increasingly important. In particular, patients treated with adjuvant chemotherapy regimens, commonly including alkylating agents and anthracyclines, are at increased risk of developing leukemia, further enhanced by the use of radiotherapy. In the last few years also the use of growth factors seems to increase the risk of secondary leukemia. The purpose of this review is to update epidemiology of therapy-related myeloid neoplasms occurring in breast cancer patients.
    Mediterranean Journal of Hematology and Infectious Diseases 01/2011; 3(1):e2011069. DOI:10.4084/MJHID.2011.069
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