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Prepublished online as a Blood First Edition Paper on June 19, 2003; DOI 10.1182/blood-2002-12-3627. This Article Full Text (PDF) All Versions of this Article: 2002-12-3627v1 102/7/2387    most recent Alert me when this article is cited Alert me if a correction is posted 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 Zwaan, C. M Articles by Griesinger, F. Search for Related Content PubMed PubMed Citation Articles by Zwaan, C. M Articles by Griesinger, F. Social Bookmarking                   What's this? Submitted December 3, 2002 Accepted June 3, 2003 FLT3 internal tandem duplication in 234 children with acute myeloid leukemia (AML): prognostic significance and relation to cellular drug resistance Christian M Zwaan*, Soheil Meshinchi, Jerald P Radich, Anjo J Veerman, Dieuwke R Huismans, Leonhard Munske, Martina Podleschny, Karel Hahlen, Rob Pieters, Martin Zimmermann, Dirk Reinhardt, Jochen Harbott, Ursula Creutzig, Gertjan J Kaspers, and Frank Griesinger Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, The Netherlands Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Hematology and Oncology, University of Gottingen, Gottingen, Germany Dutch Childhood Leukemia Study Group, Den Haag, The Netherlands; Pediatric Oncology, Sophia Children's Hospital/Erasmus Medical Center, Rotterdam, The Netherlands Pediatric Oncology, Sophia Children's Hospital/Erasmus Medical Center, Rotterdam, The Netherlands AML-BFM Study Group, Munster, Germany Oncogenetic Laboratory, Children's Hospital Giessen, Giessen, Germany * Corresponding author; email: cm.zwaan{at}vumc.nl. FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3/ITD) have been reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3/ITD in 11.5% of 234 children with de novo AML. FLT3/ITD positive patients were significantly older, had more frequently normal cytogenetics and FAB M1/M2, and less frequently 11q23 abnormalities or FAB M5. FLT3/ITD positive patients had lower remission induction rates (70% vs. 88%, p=0.01), and lower 5-year probability of event free (pEFS 29% vs. 46%, p=0.0046) and overall survival (32% vs. 58%, p=0.037). Patients with high ratios between mutant and wild-type FLT3, i.e. above the median, did significantly worse in terms of 2-year EFS than FLT3/ITD negative patients (pEFS 20% vs. 61%, p=0.037), whereas patients with ratios below the median did not (pEFS 44% vs. 61%, p=0.26). FLT3/ITD was the strongest independent predictor for pEFS with an increase in relative risk for an event of 1.92 (p=0.01). We studied cellular drug resistance, using an MTT-based assay, on 15 FLT3/ITD positive and 125 FLT3/ITD negative AML samples, but we found no differences in cellular drug resistance which could explain the poor outcome of FLT3/ITD positive patients. We conclude that FLT3/ITD is less common in pediatric than in adult AML. FLT3/ITD is a strong and independent adverse prognostic factor, and high ratios between mutant and WT-FLT3 further compromise prognosis. However, poor outcome in FLT3/ITD positive patients could not be attributed to increased in-vitro cellular drug resistance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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. 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