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Best Pract Res Clin Haematol. 2009 Sep;22(3):367-79. doi: 10.1016/j.beha.2009.05.004.

Cause and management of therapy resistance.

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III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, 68167 Mannheim, Germany.


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.

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