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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2589-2596. Prepublished online as a Blood First Edition Paper on December 26, 2007; DOI 10.1182/blood-2007-09-112730. This Article Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2007-09-112730v1 111/5/2589    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 Raponi, M. Articles by Karp, J. E Search for Related Content PubMed PubMed Citation Articles by Raponi, M. Articles by Karp, J. E Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 24, 2007 Accepted December 16, 2007 A two-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia Mitch Raponi*, Jeffrey E Lancet, Hongtao Fan, Lesley Dossey, Grace Lee, Ivana Gojo, Eric J Feldman, Jason Gotlib, Lawrence E Morris, Peter L Greenberg, John J Wright, Jean-Luc Harousseau, Bob Lowenberg, Richard M Stone, Peter De Porre, Yixin Wang, and Judith E Karp Molecular Diagnostics, Veridex, L.L.C. a Johnson and Johnson company, La Jolla, CA, United States H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, United States Clinical Pharmacology, Centocor R&D, Inc., Malvern, PA, United States Greenebaum Cancer Center, University of Maryland, Baltimore, MD, United States Weill Medical College, Cornell University, New York, NY, United States Stanford Cancer Center, Stanford, CA, United States Blood and Bone Marrow Transplant Group of Georgia, Northside Hospital, Atlanta, GA, United States Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, United States Service d'Hematologie Clinique, CHRU Hotel Dieu, Nantes, France Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, MA, United States Oncology Development, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Beerse, Belgium The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States * Corresponding author; email: mraponi1{at}ocdus.jnj.com. Currently there is no method available to predict response to farnesyltransferase inhibitors (FTI). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib, in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1:APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a leave-one-out cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days, p = 0.0001), which was independent of other co-variates including a previously described prognostic gene expression classifier. Therefore, these data indicate that a two-gene expression assay may have utility in categorizing a population of AML patients who are more likely to respond to tipifarnib. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-L. Harousseau, G. Martinelli, W. W. Jedrzejczak, J. M. Brandwein, D. Bordessoule, T. Masszi, G. J. Ossenkoppele, J. A. Alexeeva, G. Beutel, J. Maertens, et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older Blood, August 6, 2009; 114(6): 1166 - 1173. [Abstract] [Full Text] [PDF] U. Bacher, A. Kohlmann, and T. Haferlach Perspectives of gene expression profiling for diagnosis and therapy in haematological malignancies Brief Funct Genomic Proteomic, May 27, 2009; (2009) elp011v1. [Abstract] [Full Text] [PDF] J. E. Karp, K. Flatten, E. J. Feldman, J. M. Greer, D. A. Loegering, R. M. Ricklis, L. E. Morris, E. Ritchie, B. D. Smith, V. Ironside, et al. Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide Blood, May 14, 2009; 113(20): 4841 - 4852. [Abstract] [Full Text] [PDF] G. J. Roboz Treatment of Elderly Patients with Acute Myeloid Leukemia: Lowering the Intensity ASCO Educational Book, January 1, 2009; 2009(1): 378 - 383. [Abstract] [Full Text] [PDF] T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF]

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