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ABSTRACT
The introduction of imatinib mesylate (Gleevec) has dramatically changed the management and prognostic outlook of patients with chronic myeloid leukemia (CML). Despite the outstanding results achieved with imatinib, approximately 20% to 30% of patients may either not respond to therapy or eventually develop resistance or intolerance to the drug. Resistance to imatinib is mediated to a great extent by the emergence of mutations within the tyrosine kinase domain of the BCR-ABL oncogene. A growing number of tyrosine kinase inhibitors (TKIs) with different pharmacokinetic and pharmacodynamic profiles are currently being investigated in clinical trials to determine their efficacy against CML resistant to imatinib therapy. The leading examples of this group of second-generation TKIs are nilotinib (Tasigna) and dasatinib (Sprycel). This review addresses the causes and consequences of imatinib resistance and current management of refractory CML with the second-generation TKIs.
In the absence of effective therapy, patients with chronic-phase chronic myeloid leukemia (CML) invariably progress to a more aggressive phase of the disease termed blastic phase, typically preceded by an accelerated phase of variable duration.[1] The hallmark of the accelerated phase and particularly of the blastic phase is an unregulated overproduction of cells of myeloid origin with an increasing representation of immature forms as the disease progresses. Thus, patients in blastic phase present with a peripheral blood or bone marrow blast percentage of 30% or higher.[1] The estimated risk of transformation to the blastic phase is 5% to 10% per year during the first 2 years after diagnosis and increases to up to 20%-25% per year thereafter.[1,2] Blastic-phase CML is usually resistant to standard chemotherapeutic agents. Prior to the introduction of targeted tyrosine kinase inhibitors (TKIs) for the treatment of CML, the median survival of patients in blastic phase was less than 6 months.
The hallmark genetic abnormality in CML is the balanced translocation t(9;22)(q34;q11.2), which results in the Philadelphia chromosome (Ph). The molecular surrogate of the Ph chromosome is the BCR-ABL hybrid oncogene,[3,4] which encodes for BCR-ABL, a tyrosine kinase with deregulated activity that has been shown to be both necessary and sufficient for the initiation and maintenance of CML.[5]
The addition of imatinib mesylate (Gleevec) to the therapeutic armamentarium for CML has dramatically changed the management and prognostic outlook of patients with...