The New England Journal of Medicine, 2010, Vol.363(26), pp.2511-2521
Background Imatinib (400 mg daily) is considered the best initial therapy for patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. However, only a minority of patients treated with imatinib have a complete molecular remission. Methods We randomly assigned 636 patients with untreated chronic-phase CML to receive imatinib alone at a dose of 400 mg daily, imatinib (400 mg daily) plus cytarabine (20 mg per square meter of body-surface area per day on days 15 through 28 of each 28-day cycle) or pegylated interferon (peginterferon) alfa-2a (90 μg weekly), or imatinib alone at a dose of 600 mg daily. Molecular and cytogenetic responses, time to treatment failure, overall and event-free survival, and adverse events were assessed. An analysis of molecular response at 12 months was planned. A superior molecular response was defined as a decrease in the ratio of transcripts of the tyrosine kinase gene BCR-ABL to transcripts of ABL of 0.01% or less, corresponding to a reduction of 4 log 10 units or more from the baseline level, as assessed by means of a real-time quantitative polymerase-chain-reaction assay. Results At 12 months, the rates of cytogenetic response were similar among the four groups. The rate of a superior molecular response was significantly higher among patients receiving imatinib and peginterferon alfa-2a (30%) than among patients receiving 400 mg of imatinib alone (14%) (P=0.001). The rate was significantly higher among patients treated for more than 12 months than among those treated for 12 months or less. Gastrointestinal events were more frequent among patients receiving cytarabine, whereas rash and depression were more frequent among patients receiving peginterferon alfa-2a. Conclusions As compared with other treatments, the addition of peginterferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT00219739 .) In this study, adding pegylated interferon alfa-2a to imatinib therapy for chronic myeloid leukemia resulted in a greater reduction in the number of cells bearing BCR-ABL in a higher fraction of patients than did imatinib alone. However, pegylated interferon alfa-2a also has toxic effects. Chronic myeloid leukemia (CML) is characterized by translocation t(9;22)(q34;q11) — which causes the Philadelphia chromosome — on which a BCR-ABL fusion gene codes for a protein with constitutive tyrosine kinase activity.1–3 Imatinib, a rationally designed tyrosine kinase inhibitor, has shown activity against leukemic cells in vitro and in vivo.4,5 On the basis of the results of the large phase 3 International Randomized Study of Interferon and STI571 (IRIS; ClinicalTrials.gov number, NCT00006343), imatinib is recommended as first-line therapy.6,7 However, in some patients, the response to imatinib is not optimal and the risk of blast crisis is increased.8 The . . .
Adult–Chemically Induced ; Anemia–Adverse Effects ; Antineoplastic Combined Chemotherapy Protocols–Therapeutic Use ; Antineoplastic Combined Chemotherapy Protocols–Administration & Dosage ; Benzamides–Adverse Effects ; Cytarabine–Analysis ; Cytarabine–Genetics ; Female–Administration & Dosage ; Fusion Proteins, Bcr-Abl–Adverse Effects ; Fusion Proteins, Bcr-Abl–Drug Therapy ; Humans–Mortality ; Interferon-Alpha–Pathology ; Interferon-Alpha–Chemically Induced ; Leukemia, Myeloid, Chronic-Phase–Administration & Dosage ; Leukemia, Myeloid, Chronic-Phase–Adverse Effects ; Leukemia, Myeloid, Chronic-Phase–Administration & Dosage ; Male–Adverse Effects ; Middle Aged–Analysis ; Neutropenia–Genetics ; Piperazines–Administration & Dosage ; Piperazines–Adverse Effects ; Polyethylene Glycols–Analysis ; Polyethylene Glycols–Drug Effects ; Proto-Oncogene Proteins C-Abl–Chemically Induced ; Proto-Oncogene Proteins C-Abl–Chemically Induced ; Pyrimidines–Chemically Induced ; Pyrimidines–Chemically Induced ; RNA, Neoplasm–Chemically Induced ; Recombinant Proteins–Chemically Induced ; Remission Induction–Chemically Induced ; Stem Cells–Chemically Induced ; Survival Analysis–Chemically Induced ; Thrombocytopenia–Chemically Induced ; Transcription, Genetic–Chemically Induced ; Treatment Outcome–Chemically Induced ; Philadelphia Pennsylvania ; Leukemia ; Manuscripts ; Kinases ; Medical Research ; Benzamides ; Interferon-Alpha ; Piperazines ; Polyethylene Glycols ; Pyrimidines ; RNA, Neoplasm ; Recombinant Proteins ; Peginterferon Alfa-2a ; Cytarabine ; Interferon Alfa-2a ; Imatinib ; Fusion Proteins, Bcr-Abl ; Proto-Oncogene Proteins C-Abl;