title: In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib.
abstract: We sought kinase domain (KD) mutations at the start of treatment with dasatinib in 46 chronic myeloid leukemia (CML) patients resistant to or intolerant of imatinib. We identified BCR-ABL mutant subclones in 12 (26%) cases and used pyrosequencing to estimate subsequent changes in their relative size after starting dasatinib. Four patients lost their mutations, which remained undetectable, 3 patients retained the original mutation or lost it only transiently, 3 lost their original mutations but acquired a new mutation (F317L), and 2 developed another mutation (T315I) in addition to the original mutation within the same subclone. This study shows that expansion of a mutant Ph-positive clone that responds initially to a second generation tyrosine kinase inhibitor may be due either to late acquisition of a second mutation in the originally mutated clone, such as the T315I, or to acquisition of a completely new mutant clone, such as F317L.
authors.affiliation: Department of Haematology, Hammersmith Hospitals Trust and Imperial College London, London, United Kingdom.
authors.forename: Jamshid S
authors.initials: JS
authors.lastname: Khorashad
authors.forename: Dragana
authors.initials: D
authors.lastname: Milojkovic
authors.forename: Puja
authors.initials: P
authors.lastname: Mehta
authors.forename: Mona
authors.initials: M
authors.lastname: Anand
authors.forename: Sara
authors.initials: S
authors.lastname: Ghorashian
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Reid
authors.forename: Valeria
authors.initials: V
authors.lastname: De Melo
authors.forename: Anna
authors.initials: A
authors.lastname: Babb
authors.forename: Hugues
authors.initials: H
authors.lastname: de Lavallade
authors.forename: Eduardo
authors.initials: E
authors.lastname: Olavarria
authors.forename: David
authors.initials: D
authors.lastname: Marin
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kaeda
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D014158:Transcription, Genetic; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib