Cause and management of therapy resistance.
A minority of patients treated with imatinib are either refractory to imatinib or eventually relapse. Relapse frequently depends on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression. Over 90 point mutations coding for single amino acid substitutions in the BCR-ABL kinase domain have been isolated from CML patients resistant to imatinib treatment. These mutations affect amino acids involved in imatinib binding or in regulatory regions of the BCR-ABL kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. The early detection of BCR-ABL mutants during therapy may aid in risk stratification as well as molecular-based treatment decisions. Therapeutic strategies of imatinib resistant disease include novel tyrosine kinase inhibitors with activity against imatinib-resistant mutations and/or with inhibition of alternative pathways, dose escalation to optimise imatinib levels, treatment interruption to stop selection of resistant cells and allogeneic stem cell transplantation in eligible patients.
Hochhaus
Andreas
A
III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, 68167 Mannheim, Germany. hochhaus@uni-hd.de
Schenk
Thomas
T
Erben
Philipp
P
Ernst
Thomas
T
La Rosée
Paul
P
Müller
Martin C
MC
D019468:Disease Management; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000628:therapy*; D010597:Pharmacogenetics / Q000379:methods*; D017354:Point Mutation