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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2589-2597. Prepublished online as a Blood First Edition Paper on July 30, 2009; DOI 10.1182/blood-2009-05-224071. This Article Full Text Full Text (PDF) Supplemental Table and Figure All Versions of this Article: blood-2009-05-224071v1 114/13/2589    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Zenz, T. Articles by Stilgenbauer, S. PubMed PubMed Citation Articles by Zenz, T. Articles by Stilgenbauer, S. Related Collections Lymphoid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial Thorsten Zenz1, Sonja Häbe1, Tina Denzel1, Julia Mohr1, Dirk Winkler1, Andreas Bühler1, Antonio Sarno1, Silja Groner1, Daniel Mertens1, Raymonde Busch2, Michael Hallek3, Hartmut Döhner1, and Stephan Stilgenbauer1 1 Department of Internal Medicine III, University of Ulm, Ulm; 2 Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich; and 3 Department of Internal Medicine I, University of Cologne, Cologne, Germany The prognosis of fludarabine (F)–refractory chronic lymphocytic leukemia (CLL) is very poor, and underlying mechanisms are only partly understood. To assess the contribution of p53 abnormalities to F-refractory CLL, we studied TP53 mutations in the CLL2H trial (subcutaneous alemtuzumab; n = 99). We found TP53 mutations in 37% of patients. Twelve of 67 (18%) patients without the 17p deletion showed a TP53 mutation and 50% showed evidence of uniparental disomy. A total of 75% of cases with TP53 mutation (without 17p–) showed clonal evolution/expansion. TP53 mutations had no impact on overall survival (P = .48). CLL with the 17p deletion or TP53 mutation showed very low miR-34a expression. To investigate the mechanisms underlying refractory CLL beyond p53, we studied cases without 17p–/TP53 mutation in detail. In several paired samples before and after F-refractory disease, no change in p21/p53 induction was observed after DNA damage. Although TP53 mutations and 17p deletions are found in a high proportion of F-refractory CLL, more than half of the cases cannot be explained by p53 defects (deletion or mutation), and alternative mechanisms need to be investigated. Alemtuzumab is effective irrespective of genetic high-risk subgroups with TP53 mutations. These clinical trials are registered at www.clinicaltrials.gov as #NCT00274976 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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