Molecular monitoring and mutation analysis of patients with advanced phase CML and Ph+ ALL receiving dasatinib.
As a result of the excellent responses achieved in chronic phase chronic myeloid leukemia since the introduction of imatinib, sensitive techniques such as reverse transcriptase real-time PCR are warranted to monitor patients receiving tyrosine kinase inhibitors (TKI). Our objective was to determine the value of molecular monitoring Ph-positive leukemias under dasatinib treatment. We used real-time PCR and ABL1 kinase domain sequencing on sequential samples from 11 patients with Philadelphia-positive leukemias who received dasatinib. We were able to detect pre-existing mutations in the kinase domain of BCR-ABL1 in four patients, particularly in patients with high BCR-ABL1 transcript levels. Most mutations disappeared with dasatinib, however, in five patients a clone with T315I appeared during dasatinib treatment. We conclude that sensitive molecular monitoring with real-time PCR for BCR-ABL1 transcripts and mutation screening of the ABL1 kinase domain of patients with Philadelphia-positive leukemias are valuable for patient management, however, mutation findings should be interpreted with caution, as mutant clones not always behave in vivo as predicted by in vitro assays.
Olsson-Strömberg
Ulla
U
Department of Hematology, University Hospital, Uppsala, Sweden. ulla.olsson.stromberg@akademiska.se
Hermansson
Monica
M
Lundán
Tuija
T
Ohm
Anne-Charlotte
AC
Engdahl
Ida
I
Höglund
Martin
M
Simonsson
Bengt
B
Porkka
Kimmo
K
Barbany
Gisela
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D002999:Clone Cells / Q000473:pathology; D004252:DNA Mutational Analysis; D000069439:Dasatinib; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D015465:Leukemia, Myeloid, Accelerated Phase / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000235:genetics; D013844:Thiazoles / Q000627:therapeutic use*; D055815:Young Adult
D011743:Pyrimidines; D012334:RNA, Neoplasm; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib