Although the development of imatinib resistance presents new therapeutic challenges, the fact that BCR-ABL is active in many imatinib-resistant patients suggests that the chimeric oncoprotein remains the most critical drug target in CML. Because mutations are heterogeneous, it may be difficult to find new ABL inhibitors with broad utility to overcome resistance. Knowledge of the mutations should permit the development of assays to detect drug-resistant clones before clinical relapse. Physicians who treat CML with imatinib should be aware of the potential for resistance development in their patients. Approaches to prevent or manage resistance include dose escalation and combination therapy, which are being evaluated clinically. The introduction of imatinib has resulted in major advances in the treatment of CML and Ph chromosomepositive acute lymphoblastic leukemia. Patients who receive imatinib as first-line treatment for newly diagnosed disease usually demonstrate high rates of complete hematologic and cytogenetic response that can be maintained for long periods. It is not surprising, however, that with longer follow-up, clinical resistance to imatinib monotherapy has emerged. Resistance to imatinib occurs mainly in patients who have advanced CML but resistance also has been observed in a significant minority of CP patients. Additional follow-up in imatinib-responsive and imatinib-resistant patients is awaited. Current studies indicate that BCR-ABL kinase domain mutations, which may affect imatinib binding to the oncoprotein, are the most common cause of acquired imatinib resistance [11,16,19,21,50]. Preclinical experiments have demonstrated that increased doses of imatinib can overcome resistances associated with certain mutations . Increased imatinib doses also have proved effective in overcoming clinical resistance in patients . The use of optimal doses at the earliest possible time must be viewed as essential. In addition, combination therapies designed to eradicate maximum numbers of different leukemic clones rapidly are the most promising approaches to preventing the emergence of certain types of resistance. Clinical testing of these strategies is now underway.
ASJC Scopus subject areas