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.
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: S Nishiwaki; K Imai; S Mizuta; H Kanamori; K Ohashi; T Fukuda; Y Onishi; S Takahashi; N Uchida; T Eto; H Nakamae; T Yujiri; S Mori; T Nagamura-Inoue; R Suzuki; Y Atsuta; J Tanaka Journal: Bone Marrow Transplant Date: 2015-09-21 Impact factor: 5.483
Authors: Michael W Schmitt; Justin R Pritchard; Scott M Leighow; Bella I Aminov; Lan Beppu; Daniel S Kim; J Graeme Hodgson; Victor M Rivera; Lawrence A Loeb; Jerald P Radich Journal: Clin Cancer Res Date: 2018-07-24 Impact factor: 12.531
Authors: Valentina Minieri; Marco De Dominici; Patrizia Porazzi; Samanta A Mariani; Orietta Spinelli; Alessandro Rambaldi; Luke F Peterson; Pierluigi Porcu; Marja T Nevalainen; Bruno Calabretta Journal: Cancer Res Date: 2018-08-28 Impact factor: 12.701
Authors: S Soverini; C De Benedittis; C Papayannidis; K Machova Polakova; C Venturi; D Russo; P Bresciani; A Iurlo; M Mancini; A Vitale; S Chiaretti; R Foà; E Abruzzese; F Sorà; A Kohlmann; T Haferlach; M Baccarani; M Cavo; G Martinelli Journal: Leukemia Date: 2016-02-12 Impact factor: 11.528