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Blood, 15 July 2007, Vol. 110, No. 2, pp. 727-734. Prepublished online as a Blood First Edition Paper on April 3, 2007; DOI 10.1182/blood-2006-11-052373. This Article Full Text (PDF) Supplemental Appendix All Versions of this Article: blood-2006-11-052373v1 110/2/727    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 Pfeifer, H. Articles by Ottmann, O. G. Search for Related Content PubMed PubMed Citation Articles by Pfeifer, H. Articles by Ottmann, O. G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 1, 2006 Accepted February 24, 2007 Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) Heike Pfeifer, Barbara Wassmann, Anna Pavlova, Lydia Wunderle, Johannes Oldenburg, Anja Binckebanck, Thoralf Lange, Andreas Hochhaus, Silvia Wystub, Patrick Bruck, Dieter Hoelzer, and Oliver G. Ottmann* Center for Internal Medicine, Dept of Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany Institute for Transfusion Medicine & Immunohematology, Red Cross Blood Donor Service Baden-Wuerttemberg-Hessen, Frankfurt, Germany Center for Internal Medicine, Dept of Hematology/Oncology, University of Leipzig, Leipzig, Germany III. Medizinische Klinik, Dept of Hematology/Oncology, Universitatsklinikum Mannheim, Ruprecht-Karls-Universitat Heidelberg, Mannheim, Germany * Corresponding author; email: ottmann{at}em.uni-frankfurt.de. Acquired imatinib resistance in advanced Philadelphia positive acute lymphoblastic leukemia (Ph+ALL) has been associated with mutations in the kinase domain (KD) of BCR-ABL. We examined the prevalence of KD mutations in newly diagnosed and imatinib naive Ph+ALL patients and assessed their clinical relevance in the setting of uniform front-line therapy. with imatinib in combination with chemotherapy. Patients enrolled in GMALL trial ADE10 for newly diagnosed elderly Ph+ALL were retrospectively examined for the presence of BCR-ABL KD mutations by denaturing high-performance liquid chromatography (D-HPLC), cDNA sequencing and allel-specific PCR. A KD mutation was detected in a minor subpopulation of leukemic cells in 40% of newly diagnosed and imatinib naive patients. At relapse, the dominant cell clone harbored an identical mutation in 90% of cases, the overall prevalence of mutations at relapse was 80%. P-loop mutations predominated and were not associated with an inferior hematologic or molecular remission rate or shorter remission duration compared with unmutated BCR-ABL. BCR-ABL mutations conferring high-level imatinib resistance are present in a substantial proportion of patients with de novo Ph+ ALL and eventually give rise to relapse. This provides a rationale for the front-line use of kinase inhibitors active against these BCR-ABL mutants. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Ph+ ALL: resistance seeds sown early Timothy Hughes and Susan Branford Blood 2007 110: 472. [Full Text] [PDF] This article has been cited by other articles: D. Jones, S. Kamel-Reid, D. Bahler, H. Dong, K. Elenitoba-Johnson, R. Press, N. Quigley, P. Rothberg, D. Sabath, D. Viswanatha, et al. Laboratory Practice Guidelines for Detecting and Reporting BCR-ABL Drug Resistance Mutations in Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia: A Report of the Association for Molecular Pathology J. Mol. Diagn., January 1, 2009; 11(1): 4 - 11. [Abstract] [Full Text] [PDF] M. Yanada, J. Takeuchi, I. Sugiura, H. Akiyama, N. Usui, F. Yagasaki, K. Nishii, Y. Ueda, M. Takeuchi, S. Miyawaki, et al. Karyotype at diagnosis is the major prognostic factor predicting relapse-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy Haematologica, February 1, 2008; 93(2): 287 - 290. [Abstract] [Full Text] [PDF] A. Fielding The Treatment of Adults with Acute Lymphoblastic Leukemia Hematology, January 1, 2008; 2008(1): 381 - 389. [Abstract] [Full Text] [PDF] M. Wetzler Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: On Target to Improve Outcome ASCO Educational Book, January 1, 2008; 2008(1): 275 - 279. [Abstract] [Full Text] [PDF] K. Dorshkind and O. N. Witte Linking the hematopoietic microenvironment to imatinib-resistant Ph+ B-ALL Genes & Dev., September 15, 2007; 21(18): 2249 - 2252. [Full Text] [PDF] D. A. Thomas Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges Hematology, January 1, 2007; 2007(1): 435 - 443. [Abstract] [Full Text] [PDF] H. M. Lazarus and S. Luger Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion Hematology, January 1, 2007; 2007(1): 444 - 452. [Abstract] [Full Text] [PDF]

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