Details

Autor(en) / Beteiligte

• 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, O G

Titel

Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia

Ist Teil von

• Leukemia, 2012-07, Vol.26 (7), p.1475-1481

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.