title: Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors.
abstract: Dasatinib and nilotinib are potent tyrosine kinase inhibitors (TKIs) with activity against many imatinib-resistant chronic myeloid leukemia (CML) clones with BCR-ABL kinase domain (KD) mutations, except T315I. We assessed for changes in the BCR-ABL KD mutation status in 112 patients with persistent CML who received a second-generation TKI after imatinib failure. Sixty-seven different KD mutations were detected before the start of therapy with a second TKI, with T315I seen in 15%. Equal numbers of patients received nilotinib or dasatinib following imatinib, and 18 received 3 TKIs. Response rates were similar for patients with and without mutations, regardless of mutation site except for T315I. Overall, 29 patients (26%) developed new KD mutations after therapy with a second (n = 24) or third (n = 5) TKI, but only 4 (4%) developed T315I. In 73% of cases, the KD mutations that persisted or developed following switch to new TKI were at sites also found in prior in vitro TKI mutagenesis assays. Although there is only a mild increase in mutation frequency with sequential TKI treatment, novel mutations do occur and mutation regression/acquisition/persistence generally reflects the in vitro differential sensitivity predicted for each TKI. In this study, there was no marked increase in development of T315I.
authors.affiliation: Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, 77030, USA. jcortes@mdanderson.org
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: C Cameron
authors.initials: CC
authors.lastname: Yin
authors.forename: Jianqin
authors.initials: J
authors.lastname: Shan
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Megan
authors.initials: M
authors.lastname: Breeden
authors.forename: Nubia
authors.initials: N
authors.lastname: Reeves
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Dan
authors.initials: D
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*