Abstract
Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.
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References
Grimwade D . The clinical significance of cytogenetic abnormalities in acute myeloid leukaemia. Best Pract Res Clin Haematol 2001; 14: 497–529.
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998; 92: 2322–2333.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083.
Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.
Dohner K, Dohner H . Molecular characterization of acute myeloid leukemia. Haematologica 2008; 93: 976–982.
Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.
Bacher U, Haferlach T, Alpermann T, Kern W, Schnittger S, Haferlach C . Molecular mutations are prognostically relevant in AML with intermediate risk cytogenetics and aberrant karyotype. Leukemia 2013; 27: 496–500.
Whitman SP, Caligiuri MA, Maharry K, Radmacher MD, Kohlschmidt J, Becker H et al. The MLL partial tandem duplication in adults aged 60 years and older with de novo cytogenetically normal acute myeloid leukemia. Leukemia 2012; 26: 1713–1717.
Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–2433.
Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.
Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66.
Metzeler KH, Becker H, Maharry K, Radmacher MD, Kohlschmidt J, Mrozek K et al. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 2011; 118: 6920–6929.
Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Rock J, Paschka P et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol 2011; 29: 1364–1372.
Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117: 2469–2475.
Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrozek K, Maharry K et al. Wilms’ tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 2008; 26: 4595–4602.
Mendler JH, Maharry K, Radmacher MD, Mrozek K, Becker H, Metzeler KH et al. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and microRNA expression signatures. J Clin Oncol 2012; 30: 3109–3118.
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.
Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.
Hou HA, Huang TC, Lin LI, Liu CY, Chen CY, Chou WC et al. WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood 2010; 115: 5222–5231.
Hou HA, Kuo YY, Liu CY, Chou WC, Lee MC, Chen CY et al. DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood 2012; 119: 559–568.
Tien HF, Wang CH, Lin MT, Lee FY, Liu MC, Chuang SM et al. Correlation of cytogenetic results with immunophenotype, genotype, clinical features, and ras mutation in acute myeloid leukemia. A study of 235 Chinese patients in Taiwan. Cancer Genet Cytogenet 1995; 84: 60–68.
Chou WC, Tang JL, Lin LI, Yao M, Tsay W, Chen CY et al. Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 2006; 66: 3310–3316.
Chen CY, Lin LI, Tang JL, Tsay W, Chang HH, Yeh YC et al. Acquisition of JAK2, PTPN11, and RAS mutations during disease progression in primary myelodysplastic syndrome. Leukemia 2006; 20: 1155–1158.
Chen CY, Lin LI, Tang JL, Ko BS, Tsay W, Chou WC et al. RUNX1 gene mutation in primary myelodysplastic syndrome—the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 2007; 139: 405–414.
Hou HA, Chou WC, Lin LI, Chen CY, Tang JL, Tseng MH et al. Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD. Leukemia 2008; 22: 1075–1078.
Shiah HS, Kuo YY, Tang JL, Huang SY, Yao M, Tsay W et al. Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23. Leukemia 2002; 16: 196–202.
Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res 2005; 11: 1372–1379.
Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114: 5352–5361.
Chou WC, Huang HH, Hou HA, Chen CY, Tang JL, Yao M et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood 2010; 116: 4086–4094.
Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay W et al. Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation. Blood 2010; 115: 2749–2754.
Chou WC, Lei WC, Ko BS, Hou HA, Chen CY, Tang JL et al. The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 2011; 25: 246–253.
Chou WC, Chou SC, Liu CY, Chen CY, Hou HA, Kuo YY et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011; 118: 3803–3810.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010; 28: 2348–2355.
Renneville A, Boissel N, Zurawski V, Llopis L, Biggio V, Nibourel O et al. Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer 2009; 115: 3719–3727.
Weissmann S, Alpermann T, Grossmann V, Kowarsch A, Nadarajah N, Eder C et al. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia 2012; 26: 934–942.
Renneville A, Boissel N, Nibourel O, Berthon C, Helevaut N, Gardin C et al. Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia 2012; 26: 1247–1254.
Schnittger S, Eder C, Jeromin S, Alpermann T, Fasan A, Grossmann V et al. ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 2013; 27: 82–91.
Gaidzik VI, Paschka P, Spath D, Habdank M, Kohne CH, Germing U et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group. J Clin Oncol 2012; 30: 1350–1357.
Grossmann V, Schnittger S, Kohlmann A, Eder C, Roller A, Dicker F et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 2012; 120: 2963–2972.
Cornelissen JJ, van Putten WL, Verdonck LF, Theobald M, Jacky E, Daenen SM et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 2007; 109: 3658–3666.
Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301: 2349–2361.
Suciu S, Mandelli F, de Witte T, Zittoun R, Gallo E, Labar B et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood 2003; 102: 1232–1240.
Tallman MS, Dewald GW, Gandham S, Logan BR, Keating A, Lazarus HM et al. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood 2007; 110: 409–417.
Basara N, Schulze A, Wedding U, Mohren M, Gerhardt A, Junghanss C et al. Early related or unrelated haematopoietic cell transplantation results in higher overall survival and leukaemia-free survival compared with conventional chemotherapy in high-risk acute myeloid leukaemia patients in first complete remission. Leukemia 2009; 23: 635–640.
Acknowledgements
This work was partially sponsored by Grants NSC 100-2314-B002-057-MY3, NSC 101-2325-B002-028 and NSC 100-2628-B-002003-MY3 from the National Science Council (Taiwan), DOH99-TD-C-111-001 from the Department of Health (Taiwan) and NTUH 102P06 and UN101-014 and 102-015 from the Department of Medical Research, National Taiwan University Hospital.
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H-AH was responsible for study design and plan, literature collection, data management and interpretation, statistical analysis and manuscript writing; Y-YK, M-CL and L-IL were responsible for mutation analysis and interpretation; C-YL was responsible for statistical analysis and interpretation of the statistical findings; C-CL, C-YC, W-CC, M-Y, S-YH, J-LT, B-SK, S-CH, S-JW, WT and Y-CC contributed patient samples and clinical data; Y-JL, Y-CC, M-HT, C-FH, C-WL, F-YL and M-CL performed the gene mutation and chromosomal studies and H-FT planned, designed and coordinated the study over th entire period and wrote the manuscript.
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Hou, HA., Lin, CC., Chou, WC. et al. Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia. Leukemia 28, 50–58 (2014). https://doi.org/10.1038/leu.2013.236
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DOI: https://doi.org/10.1038/leu.2013.236
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