The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia.
The BCR-ABL T315I mutation causes resistance to imatinib, nilotinib and dasatinib in chronic myeloid leukemia. Forty BCR-ABL positive patients with imatinib resistance were analyzed for T315I mutated clones after six months on nilotinib or dasatinib treatment by quantitative allele-specific ligation polymerase chain reaction with a sensitivity of 0.05%. Ligation polymerase chain reaction revealed 10 patients with more than 10(-5) BCR-ABL(T315I%)/GUS (high levels), none of whom achieved major molecular response after 12 months, and a further 8 patients with 10(-5) or below BCR-ABL(T315I%)/GUS (low levels) who all achieved major molecular response (P<0.001). A second independent group showed molecular response in one of 12 patients with high levels and 5 of 8 patients with low levels (P=0.018). Combining the groups resulted in a sensitivity and specificity of 92.9% and 87.5%, respectively. We conclude that the quantitative level of mutant T315I allele is predictive of major molecular response at 12 months on second-line nilotinib or dasatinib treatment. www.clinicaltrials.gov: CT00109707, NCT00384228, CA180013, CA180005 CA180006.
Abteilung für Hämatologie, Onkologie, Hämostaseologie, Universitätsklinikum Leipzig, Leipzig, Germany. langet@medizin.uni-leipzig.de
Thoralf
T
Lange
Thomas
T
Ernst
Franz X
FX
Gruber
Jacqueline
J
Maier
Michael
M
Cross
Martin C
MC
Müller
Dietger
D
Niederwieser
Andreas
A
Hochhaus
Markus
M
Pfirrmann
D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib