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

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    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, G. M., 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, 120(7), 1002-1009. https://doi.org/10.1002/cncr.28522