Abstract：
:Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n=26) or recurrent (n=65) Ph+ ALL, respectively (P=ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph+ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical-translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph+ ALL.
journal_name
Leukemiajournal_title
Leukemiaauthors
Pfeifer H,Lange T,Wystub S,Wassmann B,Maier J,Binckebanck A,Giagounidis A,Stelljes M,Schmalzing M,Dührsen U,Wunderle L,Serve H,Brück P,Schmidt A,Hoelzer D,Ottmann OGdoi
10.1038/leu.2012.5subject
Has Abstractpub_date
2012-07-01 00:00:00pages
1475-81issue
7eissn
0887-6924issn
1476-5551pii
leu20125journal_volume
26pub_type
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