• 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, and Giovanni Martinelli.
• Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy.
• Cancer. 2014 Apr 1; 120 (7): 1002-9.

BackgroundPatients 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.MethodsInterrogation 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.ResultsBCR-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.ConclusionsSecond-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.© 2013 American Cancer Society.

30 keywords...

hide…