Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors

Jorge Cortes, Elias Jabbour, Hagop Kantarjian, C. Cameron Yin, Jianqin Shan, Susan O'Brien, Guillermo Garcia-Manero, Francis Giles, Megan Breeden, Nubia Reeves, William G. Wierda, Dan Jones

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4005-4011
Number of pages7
JournalBlood
Volume110
Issue number12
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Fingerprint

Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein-Tyrosine Kinases
Phosphotransferases
Mutation
Therapeutics
Mutagenesis
Mutation Rate
Assays
Clone Cells
Switches

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. / Cortes, Jorge; Jabbour, Elias; Kantarjian, Hagop; Yin, C. Cameron; Shan, Jianqin; O'Brien, Susan; Garcia-Manero, Guillermo; Giles, Francis; Breeden, Megan; Reeves, Nubia; Wierda, William G.; Jones, Dan.

In: Blood, Vol. 110, No. 12, 01.12.2007, p. 4005-4011.

Research output: Contribution to journalArticle

Cortes, J, Jabbour, E, Kantarjian, H, Yin, CC, Shan, J, O'Brien, S, Garcia-Manero, G, Giles, F, Breeden, M, Reeves, N, Wierda, WG & Jones, D 2007, 'Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors', Blood, vol. 110, no. 12, pp. 4005-4011. https://doi.org/10.1182/blood-2007-03-080838
Cortes, Jorge ; Jabbour, Elias ; Kantarjian, Hagop ; Yin, C. Cameron ; Shan, Jianqin ; O'Brien, Susan ; Garcia-Manero, Guillermo ; Giles, Francis ; Breeden, Megan ; Reeves, Nubia ; Wierda, William G. ; Jones, Dan. / Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. In: Blood. 2007 ; Vol. 110, No. 12. pp. 4005-4011.
@article{dafc43bb4f024ab4a19c9932d0100ed2,
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.",
author = "Jorge Cortes and Elias Jabbour and Hagop Kantarjian and Yin, {C. Cameron} and Jianqin Shan and Susan O'Brien and Guillermo Garcia-Manero and Francis Giles and Megan Breeden and Nubia Reeves and Wierda, {William G.} and Dan Jones",
year = "2007",
month = "12",
day = "1",
doi = "10.1182/blood-2007-03-080838",
language = "English (US)",
volume = "110",
pages = "4005--4011",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "12",

}

TY - JOUR

T1 - Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors

AU - Cortes, Jorge

AU - Jabbour, Elias

AU - Kantarjian, Hagop

AU - Yin, C. Cameron

AU - Shan, Jianqin

AU - O'Brien, Susan

AU - Garcia-Manero, Guillermo

AU - Giles, Francis

AU - Breeden, Megan

AU - Reeves, Nubia

AU - Wierda, William G.

AU - Jones, Dan

PY - 2007/12/1

Y1 - 2007/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=37049003546&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37049003546&partnerID=8YFLogxK

U2 - 10.1182/blood-2007-03-080838

DO - 10.1182/blood-2007-03-080838

M3 - Article

C2 - 17785585

AN - SCOPUS:37049003546

VL - 110

SP - 4005

EP - 4011

JO - Blood

JF - Blood

SN - 0006-4971

IS - 12

ER -