Mutational analysis in chronic myeloid leukemia: When and what to do?

Department of Molecular Pathology, SA Pathology, University of Adelaide, Adelaide, South Australia, Australia.
Current opinion in hematology (Impact Factor: 3.97). 03/2011; 18(2):111-6. DOI: 10.1097/MOH.0b013e32834399ef
Source: PubMed


Imatinib, which was the first targeted therapy for patients with chronic myeloid leukemia (CML), has led to the significant prolongation of life for most patients. However, approximately 30% fail therapy. The major mechanism of acquired resistance is somatic mutation within the BCR-ABL1 kinase domain, which affects imatinib binding. Recently, more potent inhibitors have been approved that retain activity against most of the more than 100 mutations. However, some mutations remain problematic for one or more of the new inhibitors. The most frequently detected mutation, T315I, remains resistant to all of the currently approved inhibitors. More sensitive mutation techniques that focus on the detection of a limited number of specific mutations may be beneficial, but are yet to prove their clinical utility for the early detection of relapse in routine practice.
Inhibitors with alternate binding modes that may overcome T315I-associated resistance are at the preclinical stage or are undergoing clinical trial.
Each of the new, more potent kinase inhibitor drugs appear to have a partially overlapping set of mutations that confer a degree of resistance. Mutation detection techniques may need to adapt to provide clinicians with a more timely indication of mutation acquisition and pending relapse.

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    • "ongoing controversies with regard to the simple use of tables listing mutations and 50% inhibitory concentration (IC 50 ) values. Some experts believe that the latter on its own should not guide physician choices for therapy (Khorashad et al, 2006; Redaelli et al, 2009; Laneuville et al, 2010; Branford & Hughes, 2011). Data from in vitro analyses do not account for factors relevant in vivo, such as protein binding and activity of cellular influx/efflux pumps or a variety of other factors affecting clinical response to a 2G TKI, and thus generally provide an inadequate predictability of treatment response (Bixby & Talpaz, 2011). "
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    Full-text · Article · Jun 2014 · British Journal of Haematology
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    • "However, TKIs are ineffective in patients who undergo blastic transformation, and unable to eradicate CML at the stem cell level. Moreover, often clinical drug resistance can develop through the acquisition of BCR-ABL gene mutations [6], [7]. Given the promising in vitro results recently obtained with newly-shaped small molecules [12], in this study a systems biology approach was applied to assess global protein expression changes and targeted protein pathways upon treatment of K562 cells with the compounds IND_S1, MEL_T1, IND_S7 and MEL_S3. "
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