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L'identification et le rôle des cibles intracytoplasmiques ont, pour certaines d'entre elles, permis des développements spectaculaires. Les applications les plus avancées concernent les antityrosines kinases et il est possible que de nouveaux inhibiteurs soient rapidement utilisés dans d'autres syndromes myéloprolifératifs. Une meilleure compréhension du protéasome a permis des résultats intéressants dans le myélome multiple, et des développements pourraient voir le jour dans d'autres hémopathies. Pour d'autres cibles apparemment prometteuses, les applications tardent à se préciser... Tel un tireur d'élite, la thérapie ciblée idéale pourrait se vanter d'une frappe "chirurgicale", ne manquant jamais son coup, respectant les cibles non visées. La réalité est pour l'instant souvent différente : parfois, la cible semble évidente, les résultats sont hélas décevants ; d'autres fois, la maladresse du tir semble en assurer l'efficacité. Quant aux cibles logiques que constituent les MAP-kinases, la P38 kinase, les protéines de stress et la bêta-caténine, la place que prendront leurs inhibiteurs parmi les anticancéreux reste à établir. Ces cibles intracytoplasmiques sont souvent au carrefour de multiples voies ou de processus biologiques complexes. Ce volume propose au lecteur une synthèse fine et richement illustrée des connaissances actuelles sur leurs fonctions physiologiques et leur rôle dans l'oncogenèse. Un CD-Rom comprenant des illustrations couleurs inédites accompagne l'ouvrage.

L'identification et le rôle des cibles intracytoplasmiques ont, pour certaines d'entre elles, permis des développements spectaculaires. Les applications les plus avancées concernent les antityrosines kinases et il est possible que de nouveaux inhibiteurs soient rapidement utilisés dans d'autres syndromes myéloprolifératifs. Une meilleure compréhension du protéasome a permis des résultats intéressants dans le myélome multiple, et des développements pourraient voir le jour dans d'autres hémopathies. Pour d'autres cibles apparemment prometteuses, les applications tardent à se préciser... Tel un tireur d'élite, la thérapie ciblée idéale pourrait se vanter d'une frappe "chirurgicale", ne manquant jamais son coup, respectant les cibles non visées. La réalité est pour l'instant souvent différente : parfois, la cible semble évidente, les résultats sont hélas décevants ; d'autres fois, la maladresse du tir semble en assurer l'efficacité. Quant aux cibles logiques que constituent les MAP-kinases, la P38 kinase, les protéines de stress et la bêta-caténine, la place que prendront leurs inhibiteurs parmi les anticancéreux reste à établir. Ces cibles intracytoplasmiques sont souvent au carrefour de multiples voies ou de processus biologiques complexes. Ce volume propose au lecteur une synthèse fine et richement illustrée des connaissances actuelles sur leurs fonctions physiologiques et leur rôle dans l'oncogenèse. Un CD-Rom comprenant des illustrations couleurs inédites accompagne l'ouvrage.

L'identification et le rôle des cibles intracytoplasmiques ont, pour certaines d'entre elles, permis des développements spectaculaires. Les applications les plus avancées concernent les antityrosines kinases et il est possible que de nouveaux inhibiteurs soient rapidement utilisés dans d'autres syndromes myéloprolifératifs. Une meilleure compréhension du protéasome a permis des résultats intéressants dans le myélome multiple, et des développements pourraient voir le jour dans d'autres hémopathies. Pour d'autres cibles apparemment prometteuses, les applications tardent à se préciser... Tel un tireur d'élite, la thérapie ciblée idéale pourrait se vanter d'une frappe "chirurgicale", ne manquant jamais son coup, respectant les cibles non visées. La réalité est pour l'instant souvent différente : parfois, la cible semble évidente, les résultats sont hélas décevants ; d'autres fois, la maladresse du tir semble en assurer l'efficacité. Quant aux cibles logiques que constituent les MAP-kinases, la P38 kinase, les protéines de stress et la bêta-caténine, la place que prendront leurs inhibiteurs parmi les anticancéreux reste à établir. Ces cibles intracytoplasmiques sont souvent au carrefour de multiples voies ou de processus biologiques complexes. Ce volume propose au lecteur une synthèse fine et richement illustrée des connaissances actuelles sur leurs fonctions physiologiques et leur rôle dans l'oncogenèse. Un CD-Rom comprenant des illustrations couleurs inédites accompagne l'ouvrage.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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].)

Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 x 10(8)/kg with a median of 2.7 x 10(8)/kg. The PB cell dose ranged from 0.02 to 77 x 10(8)/kg with a median of 9.3 x 10(8)/kg. The median dose for patients receiving BM (2.7 x 10(8)/ kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0.92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. (Blood. 2003;102:3043-3051). (C) 2003 by The American Society of Hematology.

Recombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels greater than or equal to 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to > 42) with placebo (P < .003). The mean (+/-SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P =.075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and he

Purpose: In a prospective multicenter study, we analyzed the benefits of allogeneic bone marrow transplantation (BMT) in a nonselected group of adult patients with acute lymphoblastic leukemia (ALL) and, by a randomized trial, evaluated the effectiveness of autologous BMT over chemotherapy as postremission therapy in patients younger than 50 years who were not candidates for allogeneic BMT. Patients and methods: After induction therapy that randomized patients to receive one of two anthracycline-containing regimens, either daunorubicin (DNR) or zorubicin (ZRB), patients were assigned to postremission treatment according to age and results of HLA typing. Patients younger than 40 years with an HLA-identical sibling (group 1) were scheduled to receive cyclophosphamide 60 mg/kg on days 1 and 2, total-body irradiation (TBI), and allogeneic BMT. Patients older than 50 years (group 2) received the chemotherapy arm composed of three monthly consolidation courses (DNR or ZRB, cytarabine, and asparaginase) followed by maintenance chemotherapy (modified L10 regimen). The remaining population (group 3) was randomly assigned to receive, after the three 1-month consolidation courses, either the chemotherapy arm or autologous BMT following a conditioning regimen similar to that of group 1. Results: Of the 572 assessable patients, 436 achieved complete remission (78% +/- 2% for DNR v 74% +/- 3% for ZRB; P = .3). The estimated 3-year disease-free survival (DFS) rate for the 116 patients included in group 1 was 43% +/- 5%. Both autologous BMT (95 patients) and chemotherapy (96 patients) produced comparable 3-year DFS rates (39% +/- 5% v 32% +/- 5%) and survival durations (49% +/- 5% v 42% +/- 5%). However, late relapses after 36 months were mainly observed in the chemotherapy arm. Conclusion: This first interim analysis did not demonstrate a benefit of this autologous BMT procedure over classical maintenance chemotherapy in patients with ALL who received consolidation chemotherapy.

This article reports the results of a randomized multicentric study comparing the efficacy of antithymocyte globulin (ATG) with cyclosporin-A (CsA) as first line therapy for severe aplastic anemia (SAA). Patients were randomized to receive ATG and prednisone (PDN) or CsA; hematological response and toxicity were compared. At 3 months, patients who had no or minimal response received the alternative therapy in order to assess the value of a sequential immunosuppressive therapy for treatment of severe aplastic anemia. One hundred and sixteen patients were analysed, 60 received CsA and 56 received ATG PDN. The actuarial survival was 55% with a median follow-up time of 19 months. There was no significant difference in survival between the two groups. The main prognostic factor was the absolute neutrophil count (ANC) at entry: patients with ANC <0.2 × 109/L had a significantly lower survival when compared with patients with an ANC greater than 0.2 × 109/L (P = 0.0001). At 3 months, 16% of patients had a complete or partial response and a cross-over treatment was given to 68 patients. At 12 months, 77 patients were alive, with a complete or partial response in 47 patients. Patients who had responded to the first treatment. © 1992., SCOPUS: ar.j, info:eu-repo/semantics/published

This article reports the results of a randomized multicentric study comparing the efficacy of antithymocyte globulin (ATG) with cyclosporin-A (CsA) as first line therapy for severe aplastic anemia (SAA). Patients were randomized to receive ATG and prednisone (PDN) or CsA; hematological response and toxicity were compared. At 3 months, patients who had no or minimal response received the alternative therapy in order to assess the value of a sequential immunosuppressive therapy for treatment of severe aplastic anemia. One hundred and sixteen patients were analysed, 60 received CsA and 56 received ATG PDN. The actuarial survival was 55% with a median follow-up time of 19 months. There was no significant difference in survival between the two groups. The main prognostic factor was the absolute neutrophil count (ANC) at entry: patients with ANC <0.2 × 109/L had a significantly lower survival when compared with patients with an ANC greater than 0.2 × 109/L (P = 0.0001). At 3 months, 16% of patients had a complete or partial response and a cross-over treatment was given to 68 patients. At 12 months, 77 patients were alive, with a complete or partial response in 47 patients. Patients who had responded to the first treatment. © 1992., SCOPUS: ar.j, info:eu-repo/semantics/published

To the Editor: Antibiotic therapy for patients with fever and neutropenia remains controversial.1 The most recent trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) concluded that ceftazidime given in combination with a full course of amikacin was superior to ceftazidime plus a short course of treatment with amikacin for gram-negative bacillary bacteremias, and that the former combination should be used empirically in febrile patients with neutropenia (Dec. 31 issue).2 The response rate (81 percent) reported with the full-course amikacin regimen is similar to that reported in various studies.3 4 5 6 7 8 9 The poor response rate (48 percent) with. © 1988, Massachusetts Medical Society. All rights reserved., SCOPUS: le.j, info:eu-repo/semantics/published