The introduction of imatinib mesylate to the therapy of chronic myeloid leukemia (CML) radically changed the clinical management of patients with this disorder and ushered in the era of effective targeted therapy for this disease. The results from the initial clinical studies have established imatinib as the standard for newly diagnosed therapy of chronic phase CML. As an increasing number of patients are treated with imatinib and as the long-term follow-up data on the durability of responses to imatinib continue to evolve, attention has focused on both the development of resistance to this therapy and the potential clinical implications such resistance has on the management of this disease.

Questions regarding the ultimate efficacy of imatinib have been framed in the context of whether this agent can eliminate the clonogenic BCR/ABL-positive leukemia cell. While most patients who successfully undergo allogeneic stem cell transplantation are rendered BCR/ABL negative via reverse transcriptase poly-merase chain reaction (RT-PCR), this is generally not the case with imatinib. Instead, data suggest that quantitative PCR and the ability to induce a 3-log reduction below the baseline BCR/ABL transcript is predictive of long-term response. The results from a large randomized international study demonstrated that patients who were able to achieve a > 3-log reduction (major molecular response or MMR) in BCR/ABL by RT-PCR had a better prognosis than those who were unable to do so.1 In this trial, 58% of patients who were in complete cytogenetic remission (CCR) at the 12-month mark did not progress over the next 12 months.1 Patients who were in a CCR and who did not achieve a > 3-log reduction had a 5% chance of disease progression. In this study, however, an MMR was achieved in 39% of the patients who were randomized to imatinib therapy but only 2% of patients randomized to the IFN-a plus ara-C arm. In addition, early and prompt reduction in the BCR/ABL transcript level has been shown to be predictive of CCR.23 In another study, 106 patient samples were analyzed and the level of BCR/ABL transcript at 2 months predicted for major cytogenetic response (MCR) at 6 months. Both of these studies raise the issue of the clinical relevancy of current available surrogate endpoints and whether qualitative or quantitative measurements should be used to gauge the efficacy of therapy. While complete eradication of the leukemic clone to a level undetectable by the most sensitive method available could be the ultimate goal of therapy, the ability to achieve long-term survival may also correlate with a decrease in the amount of minimal residual disease below a "critical" level. In this scenario, trace amounts of the disease may be present, but not clinically relevant as a patient continues in complete clinical remission.

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