Primary resistance to Gleevec (Abstract)

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This is an abstract discussing the difference between primary resistance and

secondary resistance to Gleevec. Only the abstract was available. The entire

article is on PDF and there is a charge for it, if you are interested in

purchasing it. This is a timely article published in the Journal of Clinical

Oncology, Vol 27, No 22 (August 1), 2009: pp. 3642-3649

© 2009 American Society

" Purpose A subset of patients with chronic myelogenous leukemia (CML) do not

respond to the tyrosine kinase inhibitor (TKI) imatinib mesylate. Such primary

imatinib resistance is distinguished from secondary resistance which reemerges

after attainment of cytogenetic remission. Patients and Methods We studied gene

expression patterns in total WBCs using a panel of 21 genes previously

implicated in TKI handling, resistance, or progression comparing patients who

had newly diagnosed TKI-naive CML that had optimal (n = 41), or suboptimal (n =

7) responses to imatinib, or primary resistance (n = 20). Expression patterns

were compared to those in secondary TKI-resistant chronic phase CML without ABL1

kinase domain mutations (n = 29), and to lymphoid (n = 15) or myeloid blast

phase disease (n = 12).

" Results Fifteen genes in the panel distinguished blast phase from chronic phase

disease, and 12 genes distinguished newly diagnosed CML from TKI-resistant CML

without ABL1 kinase domain mutations, but only a single gene,

prostaglandin-endoperoxide synthase 1/cyclooxgenase 1 (PTGS1/COX1; P = .005),

differentiated imatinib-responsive from primary imatinib-resistant CML. The

association of primary imatinib resistance with higher transcript levels of the

drug metabolism gene PTGS1 was confirmed in a separate data set of 68 newly

diagnosed, imatinib-treated CML (P = .008). In contrast, up to 11 different

genes were identified in a multivariate model that optimally discriminated

secondary imatinib resistance lacking ABL1 kinase domain mutation from

imatinib-responsive cases, likely related to the more complex pathogenesis of

secondary resistance.

" Conclusion Gene expression profiling of CML at diagnosis for PTGS1 may be

useful in predicting imatinib response and in selecting alternate therapy.

Supported by a developmental grant from the Leukemia SPORE (1P50CA100632)

awarded by the National Cancer Institute, Department of Health and Human

Services.

http://jco.ascopubs.org/cgi/content/abstract/27/22/3642

FYI,

Lottie Duthu