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 language | English |
|---|---|
| Pages (from-to) | 1002-1009 |
| Number of pages | 8 |
| Journal | Cancer |
| Volume | 120 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2014 |
Fingerprint
Keywords
- acute lymphoblastic leukemia
- BCR-ABL mutations
- dasatinib
- imatinib
- resistance
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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. / Soverini, Simona; De Benedittis, Caterina; Papayannidis, Cristina; Paolini, Stefania; Venturi, Claudia; Iacobucci, Ilaria; Luppi, Mario; Bresciani, Paola; Salvucci, Marzia; Russo, Domenico; Sica, Simona; Orlandi, Ester; Intermesoli, Tamara; Gozzini, Antonella; Bonifacio, Massimiliano; Rigolin, Gian Matteo; Pane, Fabrizio; Baccarani, Michele; Cavo, Michele; Martinelli, Giovanni.
In: Cancer, Vol. 120, No. 7, 2014, p. 1002-1009.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
T2 - The main changes are in the type of mutations, but not in the frequency of mutation involvement
AU - Soverini, Simona
AU - De Benedittis, Caterina
AU - Papayannidis, Cristina
AU - Paolini, Stefania
AU - Venturi, Claudia
AU - Iacobucci, Ilaria
AU - Luppi, Mario
AU - Bresciani, Paola
AU - Salvucci, Marzia
AU - Russo, Domenico
AU - Sica, Simona
AU - Orlandi, Ester
AU - Intermesoli, Tamara
AU - Gozzini, Antonella
AU - Bonifacio, Massimiliano
AU - Rigolin, Gian Matteo
AU - Pane, Fabrizio
AU - Baccarani, Michele
AU - Cavo, Michele
AU - Martinelli, Giovanni
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - acute lymphoblastic leukemia
KW - BCR-ABL mutations
KW - dasatinib
KW - imatinib
KW - resistance
UR - http://www.scopus.com/inward/record.url?scp=84899422233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899422233&partnerID=8YFLogxK
U2 - 10.1002/cncr.28522
DO - 10.1002/cncr.28522
M3 - Article
C2 - 24382642
AN - SCOPUS:84899422233
VL - 120
SP - 1002
EP - 1009
JO - Cancer
JF - Cancer
SN - 0008-543X
IS - 7
ER -