Originally published as JCO Early Release 10.1200/JCO.2007.15.2058 on June 16 2008

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paschka, P. Articles by Bloomfield, C. D. Search for Related Content PubMed PubMed Citation Articles by Paschka, P. Articles by Bloomfield, C. D. Related Articles Related Article Related Editorial Related Correspondence Social Bookmarking                            What's this?

Wilms’ Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Peter Paschka, Guido Marcucci, Amy S. Ruppert, Susan P. Whitman, Krzysztof Mrózek, Kati Maharry, Christian Langer, Claudia D. Baldus, Weiqiang Zhao, Bayard L. Powell, Maria R. Baer, Andrew J. Carroll, Michael A. Caligiuri, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield

From the Division of Hematology and Oncology, Department of Internal Medicine; and Human Cancer Genetics Program, Comprehensive Cancer Center; Department of Pathology; The Ohio State University, Columbus, OH; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; and Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC; Department of Hematology and Oncology, Charité University Hospital, Campus Benjamin Franklin, Berlin, Germany; Department of Medicine, Roswell Park Cancer Institute, Buffalo; and Department of Medicine, North Shore University Hospital, Manhasset, NY; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; and Department of Medicine, University of Chicago, Chicago, IL

Corresponding author: Clara D. Bloomfield, MD, Ohio State University, Comprehensive Cancer Center, 519 James Cancer Hospital, 300 West 10th Ave, Columbus, OH 43210; e-mail: clara.bloomfield{at}osumc.edu

Purpose To analyze the prognostic impact of Wilms’ tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML).

Patients and Methods We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC.

Results Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITD^negative/NPM1^mutated as low risk v FLT3-ITD^positive and/or NPM1^wild-type as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count.

Conclusion We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML.

published online ahead of print at www.jco.org on June 16, 2008.

Supported in part by Grants No. CA77658, CA101140, CA114725, CA31946, CA33601, and CA16058 from National Cancer Institute, Bethesda, MD and by the Coleman Leukemia Research Foundation.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

• Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study
  Andreas Neubauer, Kati Maharry, Krzysztof Mrózek, Christian Thiede, Guido Marcucci, Peter Paschka, Robert J. Mayer, Richard A. Larson, Edison T. Liu, and Clara D. Bloomfield
  JCO 2008 26: 4603-4609 [Abstract] [Full Text]

Related Editorial

• Molecular Classification of Acute Myeloid Leukemia: Are We There Yet?
  Jerald P. Radich
  JCO 2008 26: 4539-4541 [Full Text]

Related Correspondence

• Comparing Apples and Oranges in Normal Karyotype Acute Myeloid Leukemia
  Bruno C. Medeiros
  JCO 2009 27: 474 [Full Text]

This article has been cited by other articles:

				C. M. Santamaria, M. C. Chillon, R. Garcia-Sanz, C. Perez, M. D. Caballero, F. Ramos, A. G. de Coca, J. M. Alonso, P. Giraldo, T. Bernal, et al. Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia Blood, July 2, 2009; 114(1): 148 - 152. [Abstract] [Full Text] [PDF]

				C. Langer, G. Marcucci, K. B. Holland, M. D. Radmacher, K. Maharry, P. Paschka, S. P. Whitman, K. Mrozek, C. D. Baldus, R. Vij, et al. Prognostic Importance of MN1 Transcript Levels, and Biologic Insights From MN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., July 1, 2009; 27(19): 3198 - 3204. [Abstract] [Full Text] [PDF]

				I. H. I. M. Hollink, M. M. van den Heuvel-Eibrink, M. Zimmermann, B. V. Balgobind, S. T. C. J. M. Arentsen-Peters, M. Alders, A. Willasch, G. J. L. Kaspers, J. Trka, A. Baruchel, et al. Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia Blood, June 4, 2009; 113(23): 5951 - 5960. [Abstract] [Full Text] [PDF]

				V. I. Gaidzik, R. F. Schlenk, S. Moschny, A. Becker, L. Bullinger, A. Corbacioglu, J. Krauter, B. Schlegelberger, A. Ganser, H. Dohner, et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group Blood, May 7, 2009; 113(19): 4505 - 4511. [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]

				B. C. Medeiros Comparing Apples and Oranges in Normal Karyotype Acute Myeloid Leukemia J. Clin. Oncol., January 20, 2009; 27(3): 474 - 474. [Full Text] [PDF]

				J. Fitzgibbon, R. Gale, R. Hills, P. Virappane, A. Burnett, T. A. Lister, and D. Linch In Reply J. Clin. Oncol., January 20, 2009; 27(3): 474 - 476. [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]