title: 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.
abstract: 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 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).
authors: Department of Hematology and Oncological Sciences L e A Seràgnoli, University of Bologna, Bologna, Italy.
authors: Simona
authors: S
authors: Soverini
authors: Alessandra
authors: A
authors: Gnani
authors: Sabrina
authors: S
authors: Colarossi
authors: Fausto
authors: F
authors: Castagnetti
authors: Elisabetta
authors: E
authors: Abruzzese
authors: Stefania
authors: S
authors: Paolini
authors: Serena
authors: S
authors: Merante
authors: Ester
authors: E
authors: Orlandi
authors: Silvia
authors: S
authors: de Matteis
authors: Antonella
authors: A
authors: Gozzini
authors: Ilaria
authors: I
authors: Iacobucci
authors: Francesca
authors: F
authors: Palandri
authors: Gabriele
authors: G
authors: Gugliotta
authors: Cristina
authors: C
authors: Papayannidis
authors: Angela
authors: A
authors: Poerio
authors: Marilina
authors: M
authors: Amabile
authors: Daniela
authors: D
authors: Cilloni
authors: Gianantonio
authors: G
authors: Rosti
authors: Michele
authors: M
authors: Baccarani
authors: Giovanni
authors: G
authors: Martinelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011743:Pyrimidines / Q000008:administration & dosage*; D012008:Recurrence; D013844:Thiazoles / Q000008:administration & dosage*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib