BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications Claudia D. Baldus, Christian Thiede, Silke Soucek, Clara D. Bloomfield, Eckhard Thiel, and Gerhard Ehninger A B S T R A C T Purpose Evaluate the impact of BAALC (brain and acute leukemia, cytoplasmic), a gene whose expression has been associated with adverse outcome in acute myeloid leukemia (AML) with normal cytogenetics, and FLT3 internal tandem duplication (ITD) mutations as independent prognostic factors in a larger study. Patients and Methods BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in pretreatment blood samples of 307 adults  60 years of age with AML with normal cytogenetics. Patients were dichotomized at BAALC’s median expression into low and high expressers. The FLT3 ITD mutant:wild-type ratio was determined by fragment analysis. Results Compared with low-BAALC patients, high-BAALC patients had a higher rate of primary resistant leukemia (16% v 6%; P = .006). High BAALC expression was associated with a higher cumulative incidence of relapse (CIR; P = .018) and an inferior overall survival (OS; 3-year OS, 36% v 54%; P = .001). On multivariable analysis, high BAALC was independently predictive of resistant disease (P = .019), and high BAALC as well as a high FLT3 mutant:wild-type ratio were confirmed as the only factors predicting a high CIR (BAALC, P = .03; FLT3, P = .01) and inferior OS (BAALC, P = .001; FLT3, P = .012). Conclusion This study strengthens BAALC expression as one of the most important prognostic factors in AML patients with normal cytogenetics. BAALC expression and FLT3 mutation status should assist in tailoring induction and postremission therapies. J Clin Oncol 24:790-797. © 2006 by American Society of Clinical Oncology INTRODUCTION Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease. Currently, cyto- genetic findings provide the most important prog- nostic information. 1,2 Approximately half of adult AML patients lack clonal chromosome aberrations at diagnosis, and although this group has an inter- mediate prognosi,s only 40% are long-term survi- vors. The identification of molecular markers that precisely differentiate a patient’s risk could improve treatment outcome by the use of sophisticated risk adaptive treatment strategies. 3,4 Genes involved in signal transduction have been the focus of molecular analyses. Mutations in the fms-like tyrosine kinase 3 (FLT3) receptor, most commonly an internal tandem duplication (ITD), are frequent in AML. 5-8 Several studies have shown that overrepresentation of the ITD relative to the wild-type FLT3 allele is especially predictive of an adverse outcome. 9-11 BAALC (brain and acute leukemia, cytoplas- mic) is a gene implicated in normal hematopoiesis and leukemia. 12 The gene, located at chromosome 8q22.3, encodes a protein of yet-unknown function. In hematopoiesis, BAALC reflects a stage-specific marker and is aberrantly expressed in a subset of acute leuke- mias. 13 High mRNA expression levels of BAALC have been shown to be an adverse risk factor in newly diagnosed AML patients with normal cytogenetics. The first study to show this included 86 de novo AML patients younger than 60 years with a more favorable FLT3 mutation status treated on Cancer and Leukemia Group B (CALGB) protocol 9621. 14 Independent confirmation is required to validate the initial results so that BAALC expression may be exploited for risk-adapted treatment stratification of AML patients with normal cytogenetics. Here we present the results of a Deutsche Studieninitiative From the Charité, Universita ¨ tsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik III, Berlin; Universi- ta ¨ tsklinikum Carl Gustav Carus, Tech- nische Universita ¨ t Dresden, Medizinische Klinik I; Universita ¨ tsklini- kum Carl Gustav Carus, Technische Universita ¨ t Dresden, Deutsche Studien- initiative Leuka ¨ mie Statistical Group, Dresden, Germany; and The Ohio State University, Comprehensive Cancer Center, Columbus, OH. Submitted February 15, 2005; accepted October 5, 2005. Supported by Leukemia Clinical Research Foundation (C.D.Bloomfield) and supported by grants from the Deut- sche Krebshilfe and the Bundesministe- rium f. Bildung u. Forschung (Kompetenznetzwerk “Akute und Chro- nische Leuka ¨ mien”; G.E.). C.D. Baldus and C. Thiede contributed equally to this work. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Claudia D. Baldus, MD, Charité, Universita ¨ tsmedi- zin Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology and Transfusion Medicine, Hindenburg- damm 30, 12203 Berlin, Germany; e-mail: claudia.baldus@charite.de. © 2006 by American Society of Clinical Oncology 0732-183X/06/2405-790/$20.00 DOI: 10.1200/JCO.2005.01.6253 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 5  FEBRUARY 10 2006 790 Downloaded from ascopubs.org by 3.230.167.52 on June 17, 2022 from 003.230.167.052 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.