"Imatinib versus Interferon Alfa plus Cytarabine in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia".The New England Journal of Medicine. 2003. 348(11):994-1004.PubMed•Full text•PDFContents1Clinical Question2Bottom Line3Major Points4Guidelines5Design6Population6.1Inclusion Criteria6.2Exclusion Criteria6.3Baseline Characteristics7Interventions8Outcomes8.1Primary Outcomes8.2Secondary Outcomes9Criticisms10Funding11Further ReadingClinical QuestionIn patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML), is imatinib more effective than interferon alfa combined with low-dose cytarabine?Bottom LineImatinib was superior to interferon alfa plus low-dose cytarabine in achieving hematologic and cytogenetic responses, tolerability, and reducing progression to accelerated-phase or blast-crisis CML in newly diagnosed chronic-phase CML.Major PointsChronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), resulting from a t(9;22) reciprocal translocation. Early treatment strategies involved interferon alfa with or without low-dose cytarabine, with moderate improvement in survival rates compared to previous therapies. Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase associated with CML pathogenesis, showed promising results in patients who had no response to interferon alfa. This pivotal trial compared imatinib to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML.GuidelinesBy the time of this study, imatinib was not yet included in the guidelines for the management of newly diagnosed CML patients as first-line therapy. Current CML treatment guidelines, however, now recommend imatinib as one of the front-line treatment options.DesignMulticenter, open-label, phase 3, randomized controlled trial.N=1106 patients with newly diagnosed chronic-phase CML.Imatinib group (n=553)Interferon alfa plus low-dose cytarabine group (n=553)Setting: 177 hospitals in 16 countries.Enrollment: June 2000-January 2001.Median follow-up: 19 months.Analysis: Intention-to-treat.Primary outcomes: Progression to accelerated-phase or blast-crisis CML or death.Secondary outcomes: Rates of complete hematologic response, major and complete cytogenetic response, safety, and tolerability.PopulationInclusion CriteriaAges 18-70 years.Diagnosis of chronic-phase, Ph-positive CML within six months before study entry.Exclusion CriteriaExtramedullary disease (except hepatosplenomegaly).Platelets <100,000/mm3 unrelated to therapy.Previous chemotherapy or investigational agent treatment.Undergone hematopoietic-cell transplantation or major surgery within the preceding four weeks.Seropositive for HIV or had another cancer within the previous five years (except basal-cell carcinoma or cervical carcinoma in situ).Clinical performance status of 3 or higher.Baseline CharacteristicsThe two study groups were comparable in most characteristics. The imatinib group had a significantly higher proportion of patients with additional chromosomal abnormalities besides Ph (12.1% vs. 7.6%).InterventionsImatinib group: 400 mg orally daily.Interferon alfa plus cytarabine group: Escalating doses of interferon alfa (target dose, 5 million U/m2/d) plus subcutaneous low-dose cytarabine, 20 mg/m2/d for 10 days/month.Concurrent administration of hydroxyurea permitted in both groups during the first six months.OutcomesPrimary OutcomesMajor cytogenetic response at 18 months: 87.1% in the imatinib group vs. 34.7% in the interferon alfa plus cytarabine group (P<0.001).Estimated rate of freedom from progression at 18 months: 96.7% in the imatinib group vs. 91.5% in the combination-therapy group (P<0.001).Secondary OutcomesComplete hematologic response: 95.3% in the imatinib group vs. 55.5% in the combination-therapy group (P<0.001).Complete cytogenetic response at 18 months: 76.2% in the imatinib group vs. 14.5% in the interferon alfa plus cytarabine group (P<0.001).CriticismsThis trial utilized an open-label design, which may introduce bias, particularly in the assessment of subjective components like adverse event reporting or quality of life.FundingSupported by Novartis, the manufacturer of imatinib. All investigators received grant support from Novartis Pharma for conducting the study.Further ReadingFurther results and additional studies would optimize management and dosing strategies for imatinib and investigate the combination of imatinib with other agents for the treatment of CML.