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
Article first published online: 30 DEC 2013
© 2013 American Cancer Society
Volume 120, Issue 7, pages 1002–1009, 1 April 2014
How to Cite
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. and 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: 1002–1009. doi: 10.1002/cncr.28522
- Issue published online: 18 MAR 2014
- Article first published online: 30 DEC 2013
- Manuscript Accepted: 13 NOV 2013
- Manuscript Revised: 18 OCT 2013
- Manuscript Received: 23 APR 2013
- BCR-ABL mutations;
- acute lymphoblastic leukemia
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.
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.
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.
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. Cancer 2014;120:1002–1009. © 2013 American Cancer Society.