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. American Cancer Society.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Caterina
authors.initials: C
authors.lastname: De Benedittis
authors.forename: Cristina
authors.initials: C
authors.lastname: Papayannidis
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolini
authors.forename: Claudia
authors.initials: C
authors.lastname: Venturi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.forename: Paola
authors.initials: P
authors.lastname: Bresciani
authors.forename: Marzia
authors.initials: M
authors.lastname: Salvucci
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.forename: Simona
authors.initials: S
authors.lastname: Sica
authors.forename: Ester
authors.initials: E
authors.lastname: Orlandi
authors.forename: Tamara
authors.initials: T
authors.lastname: Intermesoli
authors.forename: Antonella
authors.initials: A
authors.lastname: Gozzini
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonifacio
authors.forename: Gian Matteo
authors.initials: GM
authors.lastname: Rigolin
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL mutations; acute lymphoblastic leukemia; dasatinib; imatinib; resistance