Imatinib Resistanceevolution Of The Target

Published criteria defines primary resistance to ima-tinib mesylate as the inability to reach complete hema-tologic remission (CHR) by 3 months, MCR (defined as (<35% of cells positive for the BCR/ABL transcript) by 6 months, or CCR by 12 months of therapy. Approximately 20-30% of newly diagnosed patients are resistant to imatinib using such criteria.12 MD Anderson Cancer Center (MDACC) has reported that primary resistance can be reduced to about 10% by increasing the standard administered dose of imatinib to 800 mg/day.3 Acquired resistance to imatinib may, however, develop as the neoplastic cells exhibit alternative mechanisms to maintain sufficient amounts of active BCR/ABL signal to maintain growth. Clinically, acquired resistance is defined as the loss of an established hematologic, cytogenetic, or molecular response or the progression of disease to an accelerated or blas-tic phase. In the large randomized imatinib study discussed above, approximately 8% of patients had an acquired resistance to imatinib by 18 months on treatment.1

Clinical resistance may develop by several mechanisms, including BCR/ABL gene amplification, incomplete inhibition of BCR/ABL cells with the subsequent selection of resistant cells, BCR/ABL gene mutations, and possibly, increased expression of the MDR-1 gene encoded P-glycoprotein. Increased expression of BCR/ABL by chromosome or gene amplification appears to be the most common mechanism of acquired resistance in vitro.45 In the clinical setting, however, several studies have shown that another common cause of acquired resistance is the development of mutations in the kinase domain of BCR/ABL.6-8 Several groups have reported at least 20 different point mutations from the leukemic cells of patients resistant to imatinib. The two most common kinase domain mutations, T315I and E255K, change the conformation of the protein and prevent the binding of imatinib to the BCR/ABL protein.6910 Although these mutations were not identified in patient samples taken prior to initiation of therapy with imatinib, they were most likely present in undetectable quantities at the time of diagnosis. This has been shown in patients with Ph-positive ALL prior to therapy with imatinib.11

Under the selective pressure of imatinib treatment, these resistant molecules emerge, giving rise to progressive disease. When patients are identified as becoming imatinib resistant, direct sequencing of BCR/ABL can be employed to define the possible mechanism of resistance. Such a strategy may, in the future, help guide treatment decisions as alternative targets and agents become available. Table 21.1 summarizes some novel therapies for treatment of ima-tinib-resistant CML.

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