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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2776-2784. Prepublished online as a Blood First Edition Paper on October 23, 2007; DOI 10.1182/blood-2007-08-109090. This Article Full Text Full Text (PDF) Supplemental Appendix All Versions of this Article: blood-2007-08-109090v1 111/5/2776    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gale, R. E. Articles by Linch, D. C. Search for Related Content PubMed PubMed Citation Articles by Gale, R. E. Articles by Linch, D. C. Related Collections Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia Rosemary E. Gale1, Claire Green1, Christopher Allen1, Adam J. Mead1, Alan K. Burnett2, Robert K. Hills2, David C. Linch1, on behalf of the Medical Research Council Adult Leukaemia Working Party 1 Department of Haematology, Royal Free and University College Medical School, London; and 2 Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom An internal tandem duplication in the fms-like tyrosine kinase 3 gene (FLT3/ITD) is associated with poor prognosis in acute myeloid leukemia (AML), but the impact of mutant level, size, and interaction with nucleophosmin 1 (NPM1) mutations remains controversial. We evaluated these characteristics in a large cohort of young adult AML patients. There was a highly significant trend for worsening in relapse risk (RR) and overall survival (OS) with increasing FLT3/ITD mutant level (P < .001 for both), and even in the low level mutant group (1%-24% of total FLT3 alleles), RR was significantly worse than in the FLT3 wild-type (WT) group (P < .001). In multivariate analysis, mutant level was the most powerful prognostic factor for RR. Mutant size and number had no significant impact on outcome. The beneficial impact of an NPM1 mutation on RR and OS was seen in FLT3/ITD+ as well as FLT3/WT patients; both markers were highly significant independent predictors of outcome (P < .001). Stratification using both markers identified 3 prognostic groups: good (FLT3/ITD–NPM1+), intermediate (FLT3/ITD–NPM1– or FLT3/ITD+NPM1+), and poor (FLT3/ITD+NPM1–). Patients with high FLT3/ITD mutant level (greater than 50%) or FLT3/ITD+ in the absence of an NPM1 mutation may be good candidates for more experimental therapeutic approaches. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Who's dancing with FLT3? Mark Levis Blood 2008 111: 2503-2504. [Full Text] [PDF] This article has been cited by other articles: C. Haferlach, C. Mecucci, S. Schnittger, A. Kohlmann, M. Mancini, A. Cuneo, N. Testoni, G. Rege-Cambrin, A. Santucci, M. Vignetti, et al. AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features Blood, October 1, 2009; 114(14): 3024 - 3032. [Abstract] [Full Text] [PDF] R. Tang, P. Hirsch, F. Fava, S. Lapusan, C. Marzac, I. Teyssandier, J. Pardo, J.-P. Marie, and O. Legrand High Id1 expression is associated with poor prognosis in 237 patients with acute myeloid leukemia Blood, October 1, 2009; 114(14): 2993 - 3000. [Abstract] [Full Text] [PDF] P. P. Zarrinkar, R. N. Gunawardane, M. D. Cramer, M. F. Gardner, D. Brigham, B. Belli, M. W. Karaman, K. W. Pratz, G. Pallares, Q. Chao, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) Blood, October 1, 2009; 114(14): 2984 - 2992. [Abstract] [Full Text] [PDF] S. Kayser, R. F. Schlenk, M. C. Londono, F. Breitenbuecher, K. Wittke, J. Du, S. Groner, D. Spath, J. Krauter, A. Ganser, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome Blood, September 17, 2009; 114(12): 2386 - 2392. [Abstract] [Full Text] [PDF] S. Schnittger, W. Kern, C. Tschulik, T. Weiss, F. Dicker, B. Falini, C. Haferlach, and T. Haferlach Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML Blood, September 10, 2009; 114(11): 2220 - 2231. [Abstract] [Full Text] [PDF] S. Meshinchi and F. R. Appelbaum Structural and Functional Alterations of FLT3 in Acute Myeloid Leukemia Clin. Cancer Res., July 1, 2009; 15(13): 4263 - 4269. [Abstract] [Full Text] [PDF] K. W. Pratz, J. Cortes, G. J. Roboz, N. Rao, O. Arowojolu, A. Stine, Y. Shiotsu, A. Shudo, S. Akinaga, D. Small, et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response Blood, April 23, 2009; 113(17): 3938 - 3946. [Abstract] [Full Text] [PDF] B. C. Medeiros Role of CEBPA in Normal Karyotype Acute Myeloid Leukemia J. Clin. Oncol., April 20, 2009; 27(12): 2105 - 2105. [Full Text] [PDF] G. Meloni, M. Mancini, V. Gianfelici, M. P. Martelli, R. Foa, and B. Falini Late relapse of acute myeloid leukemia with mutated NPM1 after eight years: evidence of NPM1 mutation stability Haematologica, February 1, 2009; 94(2): 298 - 300. [Full Text] [PDF] T. Buchner, W. E. Berdel, C. Haferlach, T. Haferlach, S. Schnittger, C. Muller-Tidow, J. Braess, K. Spiekermann, J. Kienast, P. Staib, et al. Age-Related Risk Profile and Chemotherapy Dose Response in Acute Myeloid Leukemia: A Study by the German Acute Myeloid Leukemia Cooperative Group J. Clin. Oncol., January 1, 2009; 27(1): 61 - 69. [Abstract] [Full Text] [PDF] P. Virappane, R. Gale, R. Hills, I. Kakkas, K. Summers, J. Stevens, C. Allen, C. Green, H. Quentmeier, H. Drexler, et al. Mutation of the Wilms' Tumor 1 Gene Is a Poor Prognostic Factor Associated With Chemotherapy Resistance in Normal Karyotype Acute Myeloid Leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party J. Clin. Oncol., November 20, 2008; 26(33): 5429 - 5435. [Abstract] [Full Text] [PDF] K. H. Metzeler, M. Hummel, C. D. Bloomfield, K. Spiekermann, J. Braess, M.-C. Sauerland, A. Heinecke, M. Radmacher, G. Marcucci, S. P. Whitman, et al. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia Blood, November 15, 2008; 112(10): 4193 - 4201. [Abstract] [Full Text] [PDF] J. P. Radich Molecular Classification of Acute Myeloid Leukemia: Are We There Yet? J. Clin. Oncol., October 1, 2008; 26(28): 4539 - 4541. [Full Text] [PDF] A. Liso, F. Castiglione, A. Cappuccio, F. Stracci, R. F. Schlenk, S. Amadori, C. Thiede, S. Schnittger, P. J.M. Valk, K. Dohner, et al. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1) Haematologica, August 1, 2008; 93(8): 1219 - 1226. [Abstract] [Full Text] [PDF] A. J. Mead, R. E. Gale, R. K. Hills, M. Gupta, B. D. Young, A. K. Burnett, and D. C. Linch Conflicting data on the prognostic significance of FLT3/TKD mutations in acute myeloid leukemia might be related to the incidence of biallelic disease Blood, July 15, 2008; 112(2): 444 - 445. [Full Text] [PDF] S. Meshinchi, D. L. Stirewalt, T. A. Alonzo, T. J. Boggon, R. B. Gerbing, J. L. Rocnik, B. J. Lange, D. G. Gilliland, and J. P. Radich Structural and numerical variation of FLT3/ITD in pediatric AML Blood, May 15, 2008; 111(10): 4930 - 4933. [Abstract] [Full Text] [PDF] G. Wertheim and A. Bagg Nucleophosmin (NPM1) Mutations in Acute Myeloid Leukemia: An Ongoing (Cytoplasmic) Tale of Dueling Mutations and Duality of Molecular Genetic Testing Methodologies J. Mol. 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