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.

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.

• Authors: H Pfeifer, T Lange, S Wystub, B Wassmann, J Maier, A Binckebanck, A Giagounidis, M Stelljes, M Schmalzing, U Dührsen, L Wunderle, H Serve, P Brück, A Schmidt, D Hoelzer, O G Ottmann
• Journal: Leukemia (Leukemia) Vol. 26 Issue 7 Pg. 1475-81 (Jul 2012) ISSN: 1476-5551 [Electronic] England
• PMID: 22230800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• RNA, Messenger
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Adolescent
• Adult
• Aged
• Benzamides
• Clinical Trials, Phase II as Topic
• Drug Resistance, Neoplasm (genetics)
• Female
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics)
• Humans
• Imatinib Mesylate
• Male
• Middle Aged
• Mutation (genetics)
• Neoplasm Recurrence, Local (diagnosis, drug therapy, epidemiology, genetics)
• Philadelphia Chromosome
• Piperazines (therapeutic use)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (diagnosis, drug therapy, epidemiology, genetics)
• Prevalence
• Prognosis
• Prospective Studies
• Protein Kinase Inhibitors (therapeutic use)
• Pyrimidines (therapeutic use)
• RNA, Messenger (genetics)
• Randomized Controlled Trials as Topic
• Real-Time Polymerase Chain Reaction
• Remission Induction
• Reverse Transcriptase Polymerase Chain Reaction
• Young Adult