Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors.
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.
Cortes
Jorge
J
Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, 77030, USA. jcortes@mdanderson.org
Jabbour
Elias
E
Kantarjian
Hagop
H
Yin
C Cameron
CC
Shan
Jianqin
J
O'Brien
Susan
S
Garcia-Manero
Guillermo
G
Giles
Francis
F
Breeden
Megan
M
Reeves
Nubia
N
Wierda
William G
WG
Jones
Dan
D
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*