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Blood, 3 September 2009, Vol. 114, No. 10, pp. 2168-2171. Prepublished online as a Blood First Edition Paper on July 9, 2009; DOI 10.1182/blood-2009-01-197186. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-01-197186v1 114/10/2168    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 CrossRef Google Scholar Articles by Soverini, S. Articles by Martinelli, G. PubMed PubMed Citation Articles by Soverini, S. Articles by Martinelli, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 23, 2009 Accepted June 28, 2009 Philadelphia-positive patients who already harbour imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors Simona Soverini*, Alessandra Gnani, Sabrina Colarossi, Fausto Castagnetti, Elisabetta Abruzzese, Stefania Paolini, Serena Merante, Ester Orlandi, Silvia de Matteis, Antonella Gozzini, Ilaria Iacobucci, Francesca Palandri, Gabriele Gugliotta, Cristina Papayannidis, Angela Poerio, Marilina Amabile, Daniela Cilloni, Gianantonio Rosti, Michele Baccarani, and Giovanni Martinelli Department of Hematology and Oncological Sciences "L. e A. Seragnoli", University of Bologna, Bologna, Italy Department of Hematology, University of Rome 'Tor Vergata', Rome, Italy Division of Hematology, Policlinico S. Matteo, Pavia, Italy Department of Hematology, Universita Cattolica Sacro Cuore, Rome, Italy Hematology Unit, Careggi, University of Florence, Florence, Italy Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy * Corresponding author; email: simona.soverini{at}tin.it. Dasatinib and nilotinib are tyrosine kinase inhibitors (TKIs) developed to overcome imatinib resistance in Philadelphia-positive leukemias. To assess how Bcr-Abl kinase domain mutation status evolve during sequential therapy with these TKIs and which mutations may further develop and impair their efficacy, we monitored the mutation status of 95 imatinib-resistant patients before and during treatment with dasatinib and/or nilotinib as 2nd or 3rd TKI. We found that a) 83% of cases of relapse after an initial response are associated with emergence of newly-acquired mutations. However, the spectra of mutants conferring resistance to dasatinib or nilotinib are small and non-overlapping - except for T315I; b) patients already harboring mutations had higher likelihood of relapse associated with development of further mutations as compared to patients who did not harbor mutations (23/51 as against 8/44, respectively, for patients who relapsed on 2nd TKI; 13/20 as against 1/6, respectively, for patients who relapsed on 3rd TKI). CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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