Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.

The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy. We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events. The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events. After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)

Druker BJ ，Guilhot F ，O'Brien SG ，Gathmann I ，Kantarjian H ，Gattermann N ，Deininger MW ，Silver RT ，Goldman JM ，Stone RM ，Cervantes F ，Hochhaus A ，Powell BL ，Gabrilove JL ，Rousselot P ，Reiffers J ，Cornelissen JJ ，Hughes T ，Agis H ，Fischer T ，Verhoef G ，Shepherd J ，Saglio G ，Gratwohl A ，Nielsen JL ，Radich JP ，Simonsson B ，Taylor K ，Baccarani M ，So C ，Letvak L ，Larson RA ，IRIS Investigators ... -  《-》

Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia.

In a randomized trial, 1106 patients with chronic myeloid leukemia (CML) in chronic phase were assigned to imatinib or interferon alfa plus cytarabine as initial therapy. We measured levels of BCR-ABL transcripts in the blood of all patients in this trial who had a complete cytogenetic remission. Levels of BCR-ABL transcripts were measured by a quantitative real-time polymerase-chain-reaction assay. Results were expressed relative to the median level of BCR-ABL transcripts in the blood of 30 patients with untreated CML in chronic phase. In patients who had a complete cytogenetic remission, levels of BCR-ABL transcripts after 12 months of treatment had fallen by at least 3 log in 57 percent of those in the imatinib group and 24 percent of those in the group given interferon plus cytarabine (P=0.003). On the basis of the rates of complete cytogenetic remission of 68 percent in the imatinib group and 7 percent in the group given interferon plus cytarabine at 12 months, an estimated 39 percent of all patients treated with imatinib but only 2 percent of all those given interferon plus cytarabine had a reduction in BCR-ABL transcript levels of at least 3 log (P<0.001). For patients who had a complete cytogenetic remission and a reduction in transcript levels of at least 3 log at 12 months, the probability of remaining progression-free was 100 percent at 24 months, as compared with 95 percent for such patients with a reduction of less than 3 log and 85 percent for patients who were not in complete cytogenetic remission at 12 months (P<0.001). The proportion of patients with CML who had a reduction in BCR-ABL transcript levels of at least 3 log by 12 months of therapy was far greater with imatinib treatment than with treatment with interferon plus cytarabine. Patients in the imatinib group with this degree of molecular response had a negligible risk of disease progression during the subsequent 12 months.

Hughes TP ，Kaeda J ，Branford S ，Rudzki Z ，Hochhaus A ，Hensley ML ，Gathmann I ，Bolton AE ，van Hoomissen IC ，Goldman JM ，Radich JP ，International Randomised Study of Interferon versus STI571 (IRIS) Study Group ... -  《-》

Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.

Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 percent confidence interval, 29.3 to 40.0) in the group given interferon alfa plus cytarabine (P<0.001). The estimated rates of complete cytogenetic response were 76.2 percent (95 percent confidence interval, 72.5 to 79.9) and 14.5 percent (95 percent confidence interval, 10.5 to 18.5), respectively (P<0.001). At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7 percent in the imatinib group and 91.5 percent in the combination-therapy group (P<0.001). Imatinib was better tolerated than combination therapy. In terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML.

O'Brien SG ，Guilhot F ，Larson RA ，Gathmann I ，Baccarani M ，Cervantes F ，Cornelissen JJ ，Fischer T ，Hochhaus A ，Hughes T ，Lechner K ，Nielsen JL ，Rousselot P ，Reiffers J ，Saglio G ，Shepherd J ，Simonsson B ，Gratwohl A ，Goldman JM ，Kantarjian H ，Taylor K ，Verhoef G ，Bolton AE ，Capdeville R ，Druker BJ ，IRIS Investigators ... -  《-》

Comparison between patients with Philadelphia-positive chronic phase chronic myeloid leukemia who obtained a complete cytogenetic response within 1 year of imatinib therapy and those who achieved such a response after 12 months of treatment.

Iacobucci I ，Rosti G ，Amabile M ，Poerio A ，Soverini S ，Cilloni D ，Testoni N ，Abruzzese E ，Montefusco E ，Ottaviani E ，Iuliano F ，Russo D ，Gobbi M ，Alimena G ，Martino B ，Terragna C ，Pane F ，Saglio G ，Baccarani M ，Martinelli G ... -  《-》

Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up.

The advent of imatinib has considerably changed the treatment of chronic myeloid leukemia (CML). Early studies demonstrated high rates of hematologic and cytogenetic responses in all phases of the disease after limited observation periods. The authors evaluated long-term outcome, rates of response, and resistance in 300 patients with BCR-ABL-positive leukemias (CML in chronic phase after failure to respond to interferon-alpha [CP], n = 139; accelerated phase [AP], n = 80; myeloid blast crisis [BC], n = 76; lymphoid BC and Philadelphia chromosome-positive acute lymphoblastic leukemia, n = 5) who entered clinical trials with imatinib in a single center after an observation time of 4.5 years. In CP, hematologic remission was achieved in 97% and major (MCR) and complete cytogenetic remission (CCR) in 61% and 49% of patients, respectively. The chance to achieve MCR was higher in patients commencing imatinib earlier in the course of CML. In AP, the median survival period after the start of imatinib was 44 months, and MCR and CCR were observed in 31% and 26% of patients, respectively. In myeloid BC, the median survival period after the start of imatinib and after diagnosis of BC was 6 and 9 months, respectively. Hematologic resistance occurred in 25%, 41%, and 92% of patients in CP, AP, and myeloid BC, respectively, and was associated with BCR-ABL mutations in 45% of patients and with clonal evolution in 58% of patients. The data emphasized the need for a prolonged follow-up of patients treated with imatinib to define the clinical potential of the drug and to establish methods to optimize therapy.

Lahaye T ，Riehm B ，Berger U ，Paschka P ，Müller MC ，Kreil S ，Merx K ，Schwindel U ，Schoch C ，Hehlmann R ，Hochhaus A ... -  《CANCER》