TY - JOUR
T1 - 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
AU - Soverini, Simona
AU - Gnani, Alessandra
AU - Colarossi, Sabrina
AU - Castagnetti, Fausto
AU - Abruzzese, Elisabetta
AU - Paolini, Stefania
AU - Merante, Serena
AU - Orlandi, Ester
AU - De Matteis, Silvia
AU - Gozzini, Antonella
AU - Iacobucci, Ilaria
AU - Palandri, Francesca
AU - Gugliotta, Gabriele
AU - Papayannidis, Cristina
AU - Poerio, Angela
AU - Amabile, Marilina
AU - Cilloni, Daniela
AU - Rosti, Gianantonio
AU - Baccarani, Michele
AU - Martinelli, Giovanni
PY - 2009
Y1 - 2009
N2 - 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).
AB - 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).
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U2 - 10.1182/blood-2009-01-197186
DO - 10.1182/blood-2009-01-197186
M3 - Article
C2 - 19589924
AN - SCOPUS:70349254450
VL - 114
SP - 2168
EP - 2171
JO - Blood
JF - Blood
SN - 0006-4971
IS - 10
ER -