Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement

Simona Soverini, Caterina De Benedittis, Cristina Papayannidis, Stefania Paolini, Claudia Venturi, Ilaria Iacobucci, Mario Luppi, Paola Bresciani, Marzia Salvucci, Domenico Russo, Simona Sica, Ester Orlandi, Tamara Intermesoli, Antonella Gozzini, Massimiliano Bonifacio, Gian Matteo Rigolin, Fabrizio Pane, Michele Baccarani, Michele Cavo, Giovanni Martinelli

Research output: Contribution to journalArticle

Abstract

BACKGROUND Patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR-ABL kinase domain (KD) mutations. To analyze the changes that second-generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR-ABL KD mutation analyses performed in the authors' laboratory from January 2004 to January 2013. METHODS Interrogation of the database retrieved 450 mutation analyses in 272 patients with Ph+ ALL. Prescreening of samples was performed with denaturing high-performance liquid chromatography (D-HPLC), followed by direct sequencing of D-HPLC-positive cases. RESULTS BCR-ABL KD mutations were detected in 70% of imatinib-resistant patients, with T315I, E255K, and Y253H mutations accounting for 75% of cases. Seventy-eight percent of the patients reported to be resistant to second-generation TKIs after imatinib failure were positive for mutations, and 58% of them had multiple mutations. Analysis of patients relapsing on dasatinib revealed a newly acquired T315I mutation in almost two-thirds of the cases. Direct sequencing detected no mutations at diagnosis, even in patients who relapsed after a few months. CONCLUSIONS Second-generation TKIs ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long-term disease control remains a problem, and the T315I mutation is revealed to be an even more frequent enemy. BCR-ABL KD mutation screening of patients with Ph+ ALL who are receiving imatinib or second-generation TKIs would be a precious ally for timely treatment optimization. In contrast, the clinical usefulness of conventional direct sequencing at diagnosis seems to be very low.

Original languageEnglish
Pages (from-to)1002-1009
Number of pages8
JournalCancer
Volume120
Issue number7
DOIs
Publication statusPublished - 2014

Fingerprint

Philadelphia Chromosome
Mutation Rate
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Drug Resistance
Protein-Tyrosine Kinases
Phosphotransferases
Mutation
Imatinib Mesylate
High Pressure Liquid Chromatography
Databases
Clone Cells

Keywords

  • acute lymphoblastic leukemia
  • BCR-ABL mutations
  • dasatinib
  • imatinib
  • resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era : The main changes are in the type of mutations, but not in the frequency of mutation involvement. / Soverini, Simona; De Benedittis, Caterina; Papayannidis, Cristina; Paolini, Stefania; Venturi, Claudia; Iacobucci, Ilaria; Luppi, Mario; Bresciani, Paola; Salvucci, Marzia; Russo, Domenico; Sica, Simona; Orlandi, Ester; Intermesoli, Tamara; Gozzini, Antonella; Bonifacio, Massimiliano; Rigolin, Gian Matteo; Pane, Fabrizio; Baccarani, Michele; Cavo, Michele; Martinelli, Giovanni.

In: Cancer, Vol. 120, No. 7, 2014, p. 1002-1009.

Research output: Contribution to journalArticle

Soverini, S, De Benedittis, C, Papayannidis, C, Paolini, S, Venturi, C, Iacobucci, I, Luppi, M, Bresciani, P, Salvucci, M, Russo, D, Sica, S, Orlandi, E, Intermesoli, T, Gozzini, A, Bonifacio, M, Rigolin, GM, Pane, F, Baccarani, M, Cavo, M & Martinelli, G 2014, 'Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement', Cancer, vol. 120, no. 7, pp. 1002-1009. https://doi.org/10.1002/cncr.28522
Soverini, Simona ; De Benedittis, Caterina ; Papayannidis, Cristina ; Paolini, Stefania ; Venturi, Claudia ; Iacobucci, Ilaria ; Luppi, Mario ; Bresciani, Paola ; Salvucci, Marzia ; Russo, Domenico ; Sica, Simona ; Orlandi, Ester ; Intermesoli, Tamara ; Gozzini, Antonella ; Bonifacio, Massimiliano ; Rigolin, Gian Matteo ; Pane, Fabrizio ; Baccarani, Michele ; Cavo, Michele ; Martinelli, Giovanni. / Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era : The main changes are in the type of mutations, but not in the frequency of mutation involvement. In: Cancer. 2014 ; Vol. 120, No. 7. pp. 1002-1009.
@article{4fdc17131cbd4385889f823a43d618d0,
title = "Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement",
abstract = "BACKGROUND Patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR-ABL kinase domain (KD) mutations. To analyze the changes that second-generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR-ABL KD mutation analyses performed in the authors' laboratory from January 2004 to January 2013. METHODS Interrogation of the database retrieved 450 mutation analyses in 272 patients with Ph+ ALL. Prescreening of samples was performed with denaturing high-performance liquid chromatography (D-HPLC), followed by direct sequencing of D-HPLC-positive cases. RESULTS BCR-ABL KD mutations were detected in 70{\%} of imatinib-resistant patients, with T315I, E255K, and Y253H mutations accounting for 75{\%} of cases. Seventy-eight percent of the patients reported to be resistant to second-generation TKIs after imatinib failure were positive for mutations, and 58{\%} of them had multiple mutations. Analysis of patients relapsing on dasatinib revealed a newly acquired T315I mutation in almost two-thirds of the cases. Direct sequencing detected no mutations at diagnosis, even in patients who relapsed after a few months. CONCLUSIONS Second-generation TKIs ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long-term disease control remains a problem, and the T315I mutation is revealed to be an even more frequent enemy. BCR-ABL KD mutation screening of patients with Ph+ ALL who are receiving imatinib or second-generation TKIs would be a precious ally for timely treatment optimization. In contrast, the clinical usefulness of conventional direct sequencing at diagnosis seems to be very low.",
keywords = "acute lymphoblastic leukemia, BCR-ABL mutations, dasatinib, imatinib, resistance",
author = "Simona Soverini and {De Benedittis}, Caterina and Cristina Papayannidis and Stefania Paolini and Claudia Venturi and Ilaria Iacobucci and Mario Luppi and Paola Bresciani and Marzia Salvucci and Domenico Russo and Simona Sica and Ester Orlandi and Tamara Intermesoli and Antonella Gozzini and Massimiliano Bonifacio and Rigolin, {Gian Matteo} and Fabrizio Pane and Michele Baccarani and Michele Cavo and Giovanni Martinelli",
year = "2014",
doi = "10.1002/cncr.28522",
language = "English",
volume = "120",
pages = "1002--1009",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "7",

}

TY - JOUR

T1 - Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era

T2 - The main changes are in the type of mutations, but not in the frequency of mutation involvement

AU - Soverini, Simona

AU - De Benedittis, Caterina

AU - Papayannidis, Cristina

AU - Paolini, Stefania

AU - Venturi, Claudia

AU - Iacobucci, Ilaria

AU - Luppi, Mario

AU - Bresciani, Paola

AU - Salvucci, Marzia

AU - Russo, Domenico

AU - Sica, Simona

AU - Orlandi, Ester

AU - Intermesoli, Tamara

AU - Gozzini, Antonella

AU - Bonifacio, Massimiliano

AU - Rigolin, Gian Matteo

AU - Pane, Fabrizio

AU - Baccarani, Michele

AU - Cavo, Michele

AU - Martinelli, Giovanni

PY - 2014

Y1 - 2014

N2 - BACKGROUND Patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR-ABL kinase domain (KD) mutations. To analyze the changes that second-generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR-ABL KD mutation analyses performed in the authors' laboratory from January 2004 to January 2013. METHODS Interrogation of the database retrieved 450 mutation analyses in 272 patients with Ph+ ALL. Prescreening of samples was performed with denaturing high-performance liquid chromatography (D-HPLC), followed by direct sequencing of D-HPLC-positive cases. RESULTS BCR-ABL KD mutations were detected in 70% of imatinib-resistant patients, with T315I, E255K, and Y253H mutations accounting for 75% of cases. Seventy-eight percent of the patients reported to be resistant to second-generation TKIs after imatinib failure were positive for mutations, and 58% of them had multiple mutations. Analysis of patients relapsing on dasatinib revealed a newly acquired T315I mutation in almost two-thirds of the cases. Direct sequencing detected no mutations at diagnosis, even in patients who relapsed after a few months. CONCLUSIONS Second-generation TKIs ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long-term disease control remains a problem, and the T315I mutation is revealed to be an even more frequent enemy. BCR-ABL KD mutation screening of patients with Ph+ ALL who are receiving imatinib or second-generation TKIs would be a precious ally for timely treatment optimization. In contrast, the clinical usefulness of conventional direct sequencing at diagnosis seems to be very low.

AB - BACKGROUND Patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR-ABL kinase domain (KD) mutations. To analyze the changes that second-generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR-ABL KD mutation analyses performed in the authors' laboratory from January 2004 to January 2013. METHODS Interrogation of the database retrieved 450 mutation analyses in 272 patients with Ph+ ALL. Prescreening of samples was performed with denaturing high-performance liquid chromatography (D-HPLC), followed by direct sequencing of D-HPLC-positive cases. RESULTS BCR-ABL KD mutations were detected in 70% of imatinib-resistant patients, with T315I, E255K, and Y253H mutations accounting for 75% of cases. Seventy-eight percent of the patients reported to be resistant to second-generation TKIs after imatinib failure were positive for mutations, and 58% of them had multiple mutations. Analysis of patients relapsing on dasatinib revealed a newly acquired T315I mutation in almost two-thirds of the cases. Direct sequencing detected no mutations at diagnosis, even in patients who relapsed after a few months. CONCLUSIONS Second-generation TKIs ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long-term disease control remains a problem, and the T315I mutation is revealed to be an even more frequent enemy. BCR-ABL KD mutation screening of patients with Ph+ ALL who are receiving imatinib or second-generation TKIs would be a precious ally for timely treatment optimization. In contrast, the clinical usefulness of conventional direct sequencing at diagnosis seems to be very low.

KW - acute lymphoblastic leukemia

KW - BCR-ABL mutations

KW - dasatinib

KW - imatinib

KW - resistance

UR - http://www.scopus.com/inward/record.url?scp=84899422233&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899422233&partnerID=8YFLogxK

U2 - 10.1002/cncr.28522

DO - 10.1002/cncr.28522

M3 - Article

C2 - 24382642

AN - SCOPUS:84899422233

VL - 120

SP - 1002

EP - 1009

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 7

ER -