For patients who are not suitable candidates for ASCT, alternative therapies have historically included hydroxyurea and interferon-a; however, these agents have largely been supplanted by imatinib mesylate (or Gleevec, STI571), a synthetic tyrosine kinase inhibitor.22 Imatinib mesylate is one of the first examples of molecular-targeted drug therapy and has shown activity in all phases of CML, with substantial responses in newly diagnosed patients in chronic phase.1417 Thus far, imatinib has shown improved hematologic and cytogenetic responses, as well as a prolonged freedom from disease progression when compared to more traditional therapies. In an ongoing randomized Phase III trial (IRIS), the observed rate of complete cytoge-netic remission in newly diagnosed CML patients was 76% with imatinib versus 15% with interferon-a plus Ara-C (median follow-up, 18 months). In addition to its apparent clinical superiority, imatinib also is tolerated well, a therapeutic aspect that is in marked contrast to interferon-a,with its numerous prohibitive toxicities. Unlike imatinib and interferon-a, hydroxyurea successfully lowers the peripheral leukocyte count but neither induces a cytogenetic response nor delays disease progression,thereby limiting its role in current therapy.
Although long-term outcome data are not yet available, imatinib has emerged as the primary therapy of choice for newly diagnosed CML, though it is probably still not curative since the BCR-ABL1 fusion transcript typically persists at low levels. Persistence of molecular disease without relapse suggests attainment of a "dormant" state that may be induced and regulated by various mechanisms, including immune surveillance and impaired proliferation, that confer clonal quiescence. Recent reports suggest that high doses of imatinib (800 mg vs 400 mg) may indeed induce molecular remission in up to 28% of patients.18
Therapeutic resistance to imatinib has been documented in some patients, particularly in those with more advanced stages of disease. Mechanisms of resistance include (1) amplification of the BCR-ABL1 chimeric gene at the genomic or transcript level, (2) point mutations in the kinase domain of BCR-ABL1 that alter its responsiveness to imatinib, and (3) overexpression of multidrug resistance P-glycoprotein that transports imatinib from cells.23 Monitoring of the fusion transcript levels in this scenario allows for the early recognition of therapeutic resistance with as little as a two-fold increase predictive of resistance,24 which might prompt the implementation of alternative treatment strategies. Future molecular testing might be directed toward detection of resistance, for example, by screening for gene-specific point mutations.
Molecular techniques, therefore, encompass many aspects of laboratory testing that are critical to the overall evaluation of patients with CML and contribute to the diagnosis, assessment of therapeutic efficacy, and evaluation of minimal residual disease in these patients. The clinical context of the patient and the specific treatment modality determine the specific tests that are appropriate, and algorithms have been proposed to effectively and economically guide both laboratory diagnosis and monitoring25,26 (Figures 35-4a and b). These algorithms appropriately incorporate various test methods including cytogenetic and fluorescence in situ hybridization (FISH) analysis in addition to molecular techniques. Though this chapter focuses on molecular methodologies, particularly qualitative and quantitative RT-PCR, it is necessary to recognize the distinct, yet complementary, role that each method plays.
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