Philadelphia-positive patients who already harbor 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, Giovanni Martinelli

Research output: Contribution to journalArticlepeer-review

Abstract

Dasatinib and nilotinib are tyrosine kinase inhibitors (TKIs) developed to overcome imatinib resistance in Philadelphiapositive leukemias. To assess how Bcr-Abl kinase domain mutation status evolves 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 second or third TKI.We found that 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 nonoverlapping, except for T315I. Patients already harboring mutations had higher likelihood of relapse associated with development of further mutations compared with patients who did not harbor mutations (23 of 51 vs 8 of 44, respectively, for patients who relapsed on second TKI; 13 of 20 vs 1 of 6, respectively, for patients who relapsed on third TKI).

Original languageEnglish
Pages (from-to)2168-2171
Number of pages4
JournalBlood
Volume114
Issue number10
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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