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Imatinib mesylate (Gleevec) is the current standard of care for patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML); the randomized phase III IRIS study of imatinib versus interferon (IFN-α) plus cytarabine clearly established imatinib’s efficacy in this patient group. In addition, many IRIS trial patients who crossed over from IFN-α plus cytarabine to imatinib achieved durable responses (Journal Watch Oncology and Hematology Dec 6 2006).
To investigate whether imatinib is beneficial for patients who have received INF-α, an international team initiated imatinib treatment in 454 patients with late chronic-phase CML in whom primary therapy with IFN-α had failed. The primary study endpoint was major cytogenetic response (MCR), defined as complete (0% Philadelphia-chromosome–positive [Ph+] metaphases in bone-marrow aspirate cells) or partial (<35% Ph+ metaphases) cytogenetic remission. The median time from initial CML diagnosis to imatinib initiation was 34 months. Imatinib dose escalations (from 400 mg daily to 600 mg or 800 mg daily) were required for 253 patients.
Overall, 57% of patients achieved complete remission after a median of 8.3 months. After 5 years, 41% of patients remained in complete remission. Progression-free survival rates at 6 years were 84% for patients who achieved MCR by 12 months of imatinib therapy versus 36% for patients who had not achieved MCR by 12 months. Overall survival rates at 6 years were 92% for patients who achieved complete remission and 89% for those who achieved partial remission by 12 months; overall survival was 63% among those without MCR at 12 months (P<0.001). Serious adverse events with imatinib therapy were rare, and overall toxicity patterns were similar to those observed previously in imatinib trials.
Hochhaus A et al. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment. Blood 2008 Feb 1; 111:1039.
Comment
These results confirm that most patients with late chronic-phase CML (who are intolerant to IFN-α or in whom INF-α therapy fails) have imatinib responses that are more durable and have longer survival than similar patients did in the pre-imatinib era, when very few survived longer than 5 years. As noted in other CML trials, patients in this trial who did not achieve MCR (and, ideally, complete remission) with imatinib therapy had markedly poorer outcomes: This subgroup should be considered for treatment with one of the next-generation tyrosine kinase inhibitors — nilotinib (Tasigna) and dasatinib (Sprycel) — or for allogeneic stem-cell transplantation. PCR analyses of molecular remission and of BCR-ABL mutations that are resistant to available tyrosine kinase inhibitors also are useful to guide therapeutic recommendations.