Treatment with IFN-a resulted in a complete cytogenetic remission (i.e., 0% Philadelphia-chromosome (Ph)-positive metaphases) in 5-25% of the patients treated. A partial cytogenetic response (i.e., 1-34% Ph-positive metaphases) was achieved in 10-15% of the patients treated, for a major cytogenetic remission rate (i.e., 0-34% Ph-positive) of 30-35%.2 With the addition of other agents, particularly cytarabine, a complete cytogenetic response was achieved in up to 35% of patients and a major remission in up to 50%.3-7 Achieving a complete cytogenetic remission was associated with an improved survival: 78% of the patients who achieved a complete response are alive at 10 years.8 Patients with a partial cytogenetic remission have a survival advantage (39% at 10 years) over those with a minor cytogenetic response (i.e., 35-95% Ph-positive) or no cytogenetic response (25% at 10 years), although survival is not as favorable as that for patients achieving a complete remission. Thus, the goal of therapy in the IFN-a era became achievement of a complete cytogenetic remission, in contrast to the hematologic response, which was the goal of therapy in the hydroxyurea/busulfan era.

Among patients who achieve a complete cytoge-netic remission, there is a significant variability in terms of their molecular response. Patients who retain high levels of minimal residual disease by quantitative polymerase chain reaction (Q-PCR) have a high probability of relapse, whereas 80% of those with levels <0.045% remained in remission after 3 years.9 Furthermore, approximately 30% of patients who achieve a complete cytogenetic remission have unde-tectable disease by PCR (i.e., achieve complete molecular remission). These patients are cured from CML, with none having relapsed after a median follow-up of 10 years.8 Among those with residual disease by PCR, 40-60% have remained in cytogenetic remission after 10 years in what has been called "functional cure." Although this finding emphasizes the significance of achieving a molecular remission, it also points to the fact that some patients might live with low levels of minimal residual disease with no clinical evidence of CML. This has been attributed to immune mechanisms stimulated by IFN-a. In fact, cytotoxic T lymphocytes specific for PR1, a peptide derived from proteinase 3, which is overexpressed in CML, are found in patients in complete remission after IFN-a therapy (or SCT) but not in those without complete cytogenetic remission or those treated with chemotherapy.10 These lymphocytes may be responsible for the elimination or control of the residual leukemic cells.

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