Mutational analysis in chronic myeloid leukemia: when and what to do?
ABSTRACT 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). "
ABSTRACT: Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.British Journal of Haematology 06/2014; 167(1). DOI:10.1111/bjh.12977 · 4.96 Impact Factor
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ABSTRACT: The use of the polymerase chain reaction (PCR) was a revolutionary step in molecular biology, allowing for small amounts of genetic material to be amplified and studied. The advent of real-time PCR was a further refinement that led to reliable quantification of RNA and DNA. This allowed response monitoring and the detection of minimal residual disease, which proved to have important correlations with outcome in certain malignancies. The technology is indispensable for physicians and pathologists caring for oncology patients. In this article we will review the applications of molecular technology in the diagnosis and management of malignancies. Using chronic myeloid leukaemia (CML) as an example, technical aspects and clinical correlations will be discussed, with emphasis on the importance of quality assurance and standardisation to allow for comparability of results across laboratories. We will also examine emerging technologies that allow for high throughput and rapid turnaround of specimens and speculate how these would affect outcomes in future health care. The established and emerging molecular technologies have applications in many fields of oncology.Pathology 08/2011; 43(6):566-79. DOI:10.1097/PAT.0b013e32834a9da8 · 2.62 Impact Factor
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ABSTRACT: BCR-ABL1 mutation analysis is recommended to facilitate selection of appropriate therapy for patients with chronic myeloid leukemia after treatment with imatinib has failed, since some frequently occurring mutations confer clinical resistance to nilotinib and/or dasatinib. However, mutations could be present below the detection limit of conventional direct sequencing. We developed a sensitive, multiplexed mass spectrometry assay (detection limit, 0.05% to 0.5%) to determine the impact of low-level mutations after imatinib treatment has failed. Mutation status was assessed in 220 patients treated with nilotinib or dasatinib after they experienced resistance to imatinib. Mutations were detected by sequencing in 128 patients before commencing nilotinib or dasatinib therapy (switchover). In 64 patients, 132 additional low-level mutations were detected by mass spectrometry alone (50 of 132 mutations were resistant to nilotinib and/or dasatinib). When patients received the inhibitor for which the mutation confers resistance, 84% of the low-level resistant mutations rapidly became dominant clones detectable by sequencing, including 11 of 12 T315I mutations. Subsequent complete cytogenetic response rates were lower for patients with resistant mutations at switchover detected by sequencing (0%) or mass spectrometry alone (16%) compared with patients with other mutations or no mutations (41% and 49%, respectively; P < .001). Failure-free survival among the 100 patients with chronic phase chronic myeloid leukemia when resistant mutations were detected at switchover by sequencing or mass spectrometry alone was 0% and 0% compared with 51% and 45% for patients with other mutations or no mutations (P = .003). Detection of low-level mutations after imatinib resistance offers critical information to guide subsequent therapy selection. If an inappropriate kinase inhibitor is selected, there is a high risk of treatment failure with clonal expansion of the resistant mutant.Journal of Clinical Oncology 11/2011; 29(32):4250-9. DOI:10.1200/JCO.2011.35.0934 · 18.43 Impact Factor