In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib.
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.
Khorashad
Jamshid S
JS
Department of Haematology, Hammersmith Hospitals Trust and Imperial College London, London, United Kingdom.
Milojkovic
Dragana
D
Mehta
Puja
P
Anand
Mona
M
Ghorashian
Sara
S
Reid
Alistair G
AG
De Melo
Valeria
V
Babb
Anna
A
de Lavallade
Hugues
H
Olavarria
Eduardo
E
Marin
David
D
Goldman
John M
JM
Apperley
Jane F
JF
Kaeda
Jaspal S
JS
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
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