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1.
Ann Oncol ; 28(11): 2793-2798, 2017 Nov 01.
Article de Anglais | MEDLINE | ID: mdl-28945881

RÉSUMÉ

BACKGROUND: The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) without FLT3-ITD, biallelic CEBPA-, or NPM1 mutations (here referred to as NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML) in first complete remission (CR1). PATIENTS AND METHODS: We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. The NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML subgroup comprised 497 patients, aged 18-60 years. RESULTS: In donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3-0.9, P = 0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3-1.1, P = 0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37-0.9, P = 0.02) and relapse-free survival (HR 0.51, 95% CI 0.34-0.76; P = 0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer. CONCLUSION: Outside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate risk NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML in CR1. CINICALTRIALS.GOV IDENTIFIER: NCT00180115, NCT00180102.


Sujet(s)
Marqueurs biologiques tumoraux/génétique , Protéines liant les séquences stimulatrices de type CCAAT/génétique , Transplantation de cellules souches hématopoïétiques , Leucémie aigüe myéloïde/thérapie , Mutation , Protéines nucléaires/génétique , Tyrosine kinase-3 de type fms/génétique , Adolescent , Adulte , Femelle , Études de suivi , Humains , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/anatomopathologie , Mâle , Adulte d'âge moyen , Nucléophosmine , Pronostic , Études prospectives , Induction de rémission , Taux de survie , Transplantation homologue , Jeune adulte
2.
Ann Oncol ; 26(7): 1434-40, 2015 Jul.
Article de Anglais | MEDLINE | ID: mdl-25922062

RÉSUMÉ

BACKGROUND: For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. PATIENTS AND METHODS: A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m(2) over 1 h, every 12 h, days 1-5), or continuous infusion (CI) (150 mg/m(2) over 24 h, days 1-5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG. RESULTS: The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). CONCLUSION: A 5-day course of Ara-C 2 × 1000 mg/m(2) administered as bolus versus Ara-C 150 mg/m(2) administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML. CLINICAL TRIAL NUMBER: LN_NN_2004_39/EudraCT number 2014-000083-18.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Leucémie aigüe myéloïde/traitement médicamenteux , Récidive tumorale locale/traitement médicamenteux , Thérapie de rattrapage , Adolescent , Adulte , Sujet âgé , Cytarabine/administration et posologie , Voies d'administration de substances chimiques et des médicaments , Femelle , Études de suivi , Facteur de stimulation des colonies de granulocytes/administration et posologie , Humains , Leucémie aigüe myéloïde/mortalité , Leucémie aigüe myéloïde/anatomopathologie , Mâle , Adulte d'âge moyen , Mitoxantrone/administration et posologie , Récidive tumorale locale/mortalité , Récidive tumorale locale/anatomopathologie , Stadification tumorale , Pronostic , Études prospectives , Taux de survie , Vidarabine/administration et posologie , Vidarabine/analogues et dérivés , Jeune adulte
3.
Eur J Cancer ; 51(1): 27-36, 2015 Jan.
Article de Anglais | MEDLINE | ID: mdl-25459392

RÉSUMÉ

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.


Sujet(s)
Adénocarcinome/traitement médicamenteux , Antinéoplasiques/usage thérapeutique , Carcinome du canal pancréatique/traitement médicamenteux , Désoxycytidine/analogues et dérivés , Indoles/usage thérapeutique , Pyrroles/usage thérapeutique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antinéoplasiques/administration et posologie , Désoxycytidine/administration et posologie , Désoxycytidine/usage thérapeutique , Europe , Femelle , Humains , Indoles/administration et posologie , Mâle , Adulte d'âge moyen , Études prospectives , Pyrroles/administration et posologie , Sunitinib , Résultat thérapeutique ,
4.
Leukemia ; 29(5): 1060-8, 2015 May.
Article de Anglais | MEDLINE | ID: mdl-25434303

RÉSUMÉ

The optimal timing of allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) is controversial. We report on 1179 patients with a median age of 48 years who were randomized upfront. In the control arm, sibling HCT was scheduled in the first complete remission for intermediate-risk or high-risk AML and matched unrelated HCT in complex karyotype AML. In the experimental arm, matched unrelated HCT in first remission was offered also to patients with an FLT3-ITD (FMS-like tyrosine kinase 3-internal tandem duplication) allelic ratio >0.8, poor day +15 marrow blast clearance and adverse karyotypes. Further, allogeneic HCT was recommended in high-risk AML to be performed in aplasia after induction chemotherapy. In the intent-to-treat (ITT) analysis, superiority of the experimental transplant strategy could not be shown with respect to overall survival (OS) or event-free survival. As-treated analyses suggest a profound effect of allogeneic HCT on OS (HR 0.73; P=0.002) and event-free survival (HR 0.67; P<0.001). In high-risk patients, OS was significantly improved after allogeneic HCT in aplasia (HR 0.64; P=0.046) and after HCT in remission (HR 0.74; P=0.03). Although superiority of one study arm could not be demonstrated in the ITT analysis, secondary analyses suggest that early allogeneic HCT is a promising strategy for patients with high-risk AML.


Sujet(s)
Transplantation de cellules souches hématopoïétiques , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/thérapie , Adolescent , Adulte , Allèles , Survie sans rechute , Femelle , Régulation de l'expression des gènes dans la leucémie , Humains , Estimation de Kaplan-Meier , Caryotypage , Mâle , Adulte d'âge moyen , Récidive , Induction de rémission , Transplantation homologue , Résultat thérapeutique , Jeune adulte , Tyrosine kinase-3 de type fms/génétique , Tyrosine kinase-3 de type fms/métabolisme
5.
Cell Death Dis ; 5: e1318, 2014 Jul 10.
Article de Anglais | MEDLINE | ID: mdl-25010984

RÉSUMÉ

Significant advances have been made in the development of small molecules blocking the p53/MDM2 interaction. The Mdm2 inhibitor Nutlin-3 is restricted to tumors carrying wtp53. In contrast, RITA, a compound that binds p53, has recently been shown also to restore transcriptional functions of mtp53. As more than 50% of solid tumors carry p53 mutations, RITA promises to be a more effective therapeutic strategy than Nutlin-3. We investigated effects of RITA on apoptosis, cell cycle and induction of 45 p53 target genes in a panel of 14 cell lines from different tumor entities with different p53 status as well as primary lymphocytes and fibroblasts. Nine cell strains expressed wtp53, four harbored mtp53, and three were characterized by the loss of p53 protein. A significant induction of cell death upon RITA was observed in 7 of 16 cell lines. The nonmalignant cells in our panel were substantially less sensitive. We found that in contrast to Nultin-3, RITA is capable to induce cell death not only in tumor cells harboring wtp53 and mtp53 but also in p53-null cells. Importantly, whereas p53 has a central role for RITA-mediated effects in wtp53 cells, neither p53 nor p63 or p73 were essential for the RITA response in mtp53 or p53-null cells in our panel demonstrating that besides the known p53-dependent action of RITA in wtp53 cells, RITA can induce cell death also independently of p53 in cells harboring defective p53. We identified an important role of both p38 and JNK/SAPK for sensitivity to RITA in these cells leading to a typical caspase- and BAX/BAK-dependent mitochondrial apoptosis. In conclusion, our data demonstrate that RITA can induce apoptosis through p38 and JNK/SAPK not only in tumor cells harboring wtp53 and mtp53 but also in p53-null cells, making RITA an interesting tumor-selective drug.


Sujet(s)
Antinéoplasiques/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Furanes/pharmacologie , MAP Kinase Kinase 4/métabolisme , Protéine p53 suppresseur de tumeur/déficit , p38 Mitogen-Activated Protein Kinases/métabolisme , Caspases/génétique , Caspases/métabolisme , Lignée cellulaire tumorale , Humains , MAP Kinase Kinase 4/génétique , Transduction du signal/effets des médicaments et des substances chimiques , Protéine p53 suppresseur de tumeur/génétique , p38 Mitogen-Activated Protein Kinases/génétique
6.
Cell Death Dis ; 5: e1013, 2014 Jan 23.
Article de Anglais | MEDLINE | ID: mdl-24457957

RÉSUMÉ

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with transient response to conventional chemotherapy. We here investigated the role of the Bcl-2 homology domain 3-only protein NOXA for life-death decision in MCL. Surprisingly, NOXA (PMAIP1) mRNA and NOXA protein levels were extremely discrepant in MCL cells: NOXA mRNA was found to be highly expressed whereas NOXA protein levels were low. Chronic active B-cell receptor signaling and to a minor degree cyclin D1 overexpression contributed to high NOXA mRNA expression levels in MCL cells. The phoshatidyl-inositol-3 kinase/AKT/mammalian target of rapamycin pathway was identified as the major downstream signaling pathway involved in the maintenance of NOXA gene expression. Interestingly, MCL cells adapt to this constitutive pro-apoptotic signal by extensive ubiquitination and rapid proteasomal degradation of NOXA protein (T½âˆ¼15-30 min). In addition to the proteasome inhibitor Bortezomib, we identified the neddylation inhibitor MLN4924 and the fatty acid synthase inhibitor Orlistat as potent inducers of NOXA protein expression leading to apoptosis in MCL. All inhibitors targeted NOXA protein turnover. In contrast to Bortezomib, MLN4924 and Orlistat interfered with the ubiquitination process of NOXA protein thereby offering new strategies to kill Bortezomib-resistant MCL cells. Our data, therefore, highlight a critical role of NOXA in the balance between life and death in MCL. The discrepancy between NOXA transcript and protein levels is essential for sensitivity of MCL to ubiquitin-proteasome system inhibitors and could therefore provide a druggable Achilles' heel of MCL cells.


Sujet(s)
Lymphome à cellules du manteau/génétique , Protéines proto-oncogènes c-bcl-2/génétique , Protéines proto-oncogènes c-bcl-2/métabolisme , Apoptose , Lignée cellulaire tumorale , Régulation de l'expression des gènes tumoraux , Humains , Lymphome à cellules du manteau/métabolisme , Lymphome à cellules du manteau/physiopathologie , Phosphatidylinositol 3-kinases/métabolisme , Stabilité protéique , Protéines proto-oncogènes c-akt/métabolisme , Protéines proto-oncogènes c-bcl-2/composition chimique , Transduction du signal
7.
Br J Cancer ; 107(2): 280-6, 2012 Jul 10.
Article de Anglais | MEDLINE | ID: mdl-22699824

RÉSUMÉ

BACKGROUND: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. METHODS: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). RESULTS: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). CONCLUSION: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.


Sujet(s)
Adénocarcinome/traitement médicamenteux , Protéines du cycle cellulaire/antagonistes et inhibiteurs , Tumeurs du pancréas/traitement médicamenteux , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Protéines proto-oncogènes/antagonistes et inhibiteurs , Ptéridines/usage thérapeutique , Adénocarcinome/enzymologie , Adénocarcinome/métabolisme , Sujet âgé , Protéines du cycle cellulaire/métabolisme , Études de cohortes , Intervalles de confiance , Survie sans rechute , Femelle , Études de suivi , Humains , Mâle , Adulte d'âge moyen , Tumeurs du pancréas/enzymologie , Tumeurs du pancréas/métabolisme , Protein-Serine-Threonine Kinases/métabolisme , Protéines proto-oncogènes/métabolisme , Ptéridines/effets indésirables , Ptéridines/pharmacocinétique ,
8.
Thorac Cardiovasc Surg ; 60(1): 84-6, 2012 Feb.
Article de Anglais | MEDLINE | ID: mdl-21425056

RÉSUMÉ

Synovial sarcoma metastasis affecting the heart and infiltrating the mitral valve is a very rare pathology. We report the case of a 44-year-old male treated with chemotherapy for atypical synovial sarcoma of the oral mucosa who presented to our clinic after cardiac decompensation with a presumptive diagnosis of myxoma of the left atrium. A large necrotic tumour positive for CK 22, EMA, CD 99 and BCL-2 but negative for translocation in COBRA-FISH analysis by break-apart probe could be excised and revealed a very rare subtype of synovial sarcoma metastasis arising from the endocard of the left atrium. The tumour was resected and the mitral valve reconstructed through ring annuloplasty.


Sujet(s)
Défaillance cardiaque/étiologie , Tumeurs du coeur/complications , Tumeurs du coeur/secondaire , Tumeurs de la bouche/anatomopathologie , Sarcome synovial/complications , Sarcome synovial/secondaire , Adulte , Marqueurs biologiques tumoraux/analyse , Échocardiographie transoesophagienne , Atrium du coeur/anatomopathologie , Défaillance cardiaque/diagnostic , Défaillance cardiaque/chirurgie , Tumeurs du coeur/composition chimique , Tumeurs du coeur/génétique , Tumeurs du coeur/chirurgie , Implantation de valve prothétique cardiaque , Humains , Imagerie par résonance magnétique , Mâle , Annuloplastie mitrale , Muqueuse de la bouche/anatomopathologie , Tumeurs de la bouche/composition chimique , Tumeurs de la bouche/génétique , Sarcome synovial/composition chimique , Sarcome synovial/génétique , Sarcome synovial/chirurgie , Résultat thérapeutique
9.
Leukemia ; 25(3): 420-8, 2011 Mar.
Article de Anglais | MEDLINE | ID: mdl-21135859

RÉSUMÉ

Patients with secondary acute myeloid leukemia (sAML) are generally thought to have a poor prognosis. As there are no prognostic risk stratification models for patients with sAML available, the aim of this study was to obtain a scoring system. Prognostic factors influencing overall survival (OS) and event-free survival (EFS) were analyzed in 305 sAML patients treated in the prospective AML96 trial. The obtained prognostic scoring system was then validated in an independent patient cohort included in the AML2003 and AML60+ trials. In addition to the known risk factors for AML, age and karyotype, we identified the absolute platelet count and the Nucleophosmin 1 mutational status at diagnosis as prognostic factors of sAML patients. A pronounced distribution of sAML patients into three score groups was achieved showing a 2-year OS/EFS of 52/44% for patients in the low-risk group, 21/12% in the intermediate-risk group and 7/3% in the high-risk group (both P<0.001). Validation of this scoring system in a second independent set of sAML patients revealed similar significantly different survival results. In conclusion, for the first time, a prognostic scoring system is provided for sAML patients, allowing differential treatment strategies in the future.


Sujet(s)
Leucémie aigüe myéloïde/mortalité , Seconde tumeur primitive/mortalité , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Essais cliniques comme sujet , Femelle , Humains , Leucémie aigüe myéloïde/génétique , Modèles logistiques , Mâle , Adulte d'âge moyen , Mutation , Seconde tumeur primitive/génétique , Protéines nucléaires/génétique , Nucléophosmine , Numération des plaquettes , Pronostic , Études prospectives , Risque , Résultat thérapeutique
10.
Oncogene ; 27(31): 4380-4, 2008 Jul 17.
Article de Anglais | MEDLINE | ID: mdl-18362889

RÉSUMÉ

Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before gamma-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl-/- murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response.


Sujet(s)
Réparation de l'ADN , Protéines de fusion bcr-abl/biosynthèse , Régulation de l'expression des gènes tumoraux , Protéines proto-oncogènes c-abl/physiologie , Animaux , Antinéoplasiques/pharmacologie , Benzamides , Aberrations des chromosomes , Altération de l'ADN , Dasatinib , Fibroblastes/métabolisme , Humains , Mésilate d'imatinib , Cinétique , Agranulocytes/effets des médicaments et des substances chimiques , Agranulocytes/effets des radiations , Souris , Pipérazines/pharmacologie , Protéines proto-oncogènes c-abl/antagonistes et inhibiteurs , Pyrimidines/pharmacologie , Thiazoles/pharmacologie
11.
Leukemia ; 21(6): 1183-8, 2007 Jun.
Article de Anglais | MEDLINE | ID: mdl-17377585

RÉSUMÉ

The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40-66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9-36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1-14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.


Sujet(s)
Éosinophilie/traitement médicamenteux , Leucémie myéloïde/traitement médicamenteux , Protéines de fusion oncogènes/analyse , Pipérazines/administration et posologie , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Pyrimidines/administration et posologie , Récepteur au PDGF alpha , Facteurs de clivage et de polyadénylation de l'ARN messager , Maladie aigüe , Adulte , Sujet âgé , Benzamides , Survie sans rechute , Éosinophilie/complications , Humains , Mésilate d'imatinib , Mâle , Adulte d'âge moyen , Syndromes myéloprolifératifs/traitement médicamenteux , Nucléophosmine , Protéines de fusion oncogènes/génétique , Protein-tyrosine kinases/antagonistes et inhibiteurs , Récepteur au PDGF alpha/génétique , Induction de rémission/méthodes , Facteurs de clivage et de polyadénylation de l'ARN messager/génétique
12.
Ann Oncol ; 17(10): 1546-52, 2006 Oct.
Article de Anglais | MEDLINE | ID: mdl-16888080

RÉSUMÉ

INTRODUCTION: Sequential high dose (SHiDo) chemotherapy with stem cell support has been shown to prolong the event-free survival in patients with diffuse large B-cell lymphoma. METHODS: To confirm this result in a multicenter trial, we randomized patients with aggressive NHL, to receive either eight cycles of CHOP or SHiDo. The primary endpoint was overall survival. RESULTS: 129 evaluable patients were randomized to receive either CHOP or SHiDo: median age, 48 years; 62% male; stage III+IV: 73%; age adjusted International Prognostic Index 1/2/3: 21%/52%/27%. Toxicity grades 3+4 were more pronounced in the SHiDo-arm with 13% versus 3% of patients with fever; 34% versus 13% with infections; 13% versus 2% with esophagitis/dysphagia/gastric ulcer. The remission rates were similar in SHiDo and CHOP arms with 34%/37% complete remissions and 31%/31% partial remissions, respectively. After a median observation time of 48 months, there was no difference in overall survival at 3 years, with 46% for SHiDo and 53% for CHOP (P = 0.48). CONCLUSION: In this multicenter trial, early intensification with SHiDo did not confer any survival benefit in previously untreated patients with aggressive NHL and was associated with a higher incidence of grades 3/4 toxicity.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Lymphome malin non hodgkinien/traitement médicamenteux , Traitement néoadjuvant/méthodes , Adolescent , Adulte , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Cyclophosphamide/effets indésirables , Survie sans rechute , Relation dose-effet des médicaments , Doxorubicine/effets indésirables , Calendrier d'administration des médicaments , Études de faisabilité , Femelle , Humains , Lymphome malin non hodgkinien/mortalité , Lymphome malin non hodgkinien/anatomopathologie , Mâle , Adulte d'âge moyen , Analyse multifactorielle , Traitement néoadjuvant/effets indésirables , Prednisone/effets indésirables , Récidive , Thérapie de rattrapage , Analyse de survie , Vincristine/effets indésirables
13.
Cell Death Differ ; 12(6): 627-36, 2005 Jun.
Article de Anglais | MEDLINE | ID: mdl-15818402

RÉSUMÉ

Imatinib targets Bcr-Abl, the causative event of chronic myelogenous leukemia (CML), and addresses leukemic cells to growth arrest and cell death. The exact mechanisms responsible for imatinib-induced cell death are still unclear. We investigated the role of poly(ADP-ribose) polymerase (PARP) activity in imatinib-induced cell death in Bcr-Abl-positive cells. Imatinib leads to a rapid increase of poly(ADP-ribosyl)ation (PAR) preceding loss of integrity of mitochondrial membrane and DNA fragmentation. The effect of imatinib on PAR can be mimicked by inhibition of phosphatidylinositol 3-kinase (PI3-K) implicating a central role of the PI3-K pathway in Bcr-Abl-mediated inhibition of PAR. Importantly, inhibition of PAR in imatinib-treated cells partially prevented cell death to an extent comparable to that observed after caspase inhibition. Simultaneous blockade of both caspases and PAR revealed additive cytoprotective effects indicating that both pathways function in parallel. In conclusion, our results suggest that in addition to the well-documented caspase-dependent pathway, imatinib also induces a PARP-mediated death process.


Sujet(s)
Apoptose/effets des médicaments et des substances chimiques , Pipérazines/pharmacologie , Poly(ADP-ribose) polymerases/métabolisme , Pyrimidines/pharmacologie , ADP/métabolisme , Animaux , Annexine A5/métabolisme , Benzamides , Lignée cellulaire , Perméabilité des membranes cellulaires , ADN/génétique , Extracellular Signal-Regulated MAP Kinases/métabolisme , Protéines de fusion bcr-abl/antagonistes et inhibiteurs , Protéines de fusion bcr-abl/métabolisme , Humains , Mésilate d'imatinib , Membranes intracellulaires/effets des médicaments et des substances chimiques , Membranes intracellulaires/métabolisme , Souris , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Transduction du signal
15.
Urologe A ; 43(1): 85-92; quiz 93, 2004 Jan.
Article de Allemand | MEDLINE | ID: mdl-15179984

RÉSUMÉ

Significant advances have been achieved in the surgical treatment of localized renal cell carcinoma over recent years. However, despite significant research efforts, the prognosis is still dismal in the majority of patients with advanced disease. Treatment with IFN-ac leads to moderately increased survival. In addition, survival can be prolonged by tu-mor nephrectomy in patients with synchronous metastases. Combined treatment with IFN-a, IL-2 and 5-FU has demonstrated a survival benefit in a single randomized controlled trial. High dose IL-2 causes long-term regression in a small fraction of patients. All of these treatments, however, frequently cause significant morbidity and therefore the potential benefit has to be weighed carefully against toxicity in each individual patient. Although, in general, the results of immunotherapeutic approaches have been dis-appointing, studies using allogeneic stem cells, allogeneic mononuclear cells and vaccines clearly demonstrate, that tumor control can be achieved by means of immunological intervention. Future research will hopefully lead to the development of strategies helpful for a greater proportion of patients with this disease.


Sujet(s)
Antinéoplasiques/usage thérapeutique , Néphrocarcinome/traitement médicamenteux , Néphrocarcinome/immunologie , Immunosuppresseurs/usage thérapeutique , Immunothérapie/méthodes , Tumeurs du rein/traitement médicamenteux , Tumeurs du rein/immunologie , Humains , Guides de bonnes pratiques cliniques comme sujet , Types de pratiques des médecins , Pronostic , Résultat thérapeutique
16.
Leukemia ; 17(12): 2392-400, 2003 Dec.
Article de Anglais | MEDLINE | ID: mdl-14523462

RÉSUMÉ

We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.


Sujet(s)
Antinéoplasiques/administration et posologie , Protéines de fusion bcr-abl/génétique , Interféron alpha/administration et posologie , Leucémie myéloïde chronique BCR-ABL positive/traitement médicamenteux , Leucémie myéloïde chronique BCR-ABL positive/génétique , Pipérazines/administration et posologie , Pyrimidines/administration et posologie , Adulte , Sujet âgé , Antimétabolites antinéoplasiques/administration et posologie , Benzamides , Études croisées , Cytarabine/administration et posologie , Cytogénétique , Femelle , Humains , Mésilate d'imatinib , Leucémie myéloïde chronique BCR-ABL positive/diagnostic , Leucémie myéloïde chronique BCR-ABL positive/épidémiologie , Mâle , Adulte d'âge moyen , Pronostic , Études prospectives , ARN messager/métabolisme , Récidive , Facteurs de risque , Résultat thérapeutique
17.
Cytometry B Clin Cytom ; 53(1): 11-9, 2003 May.
Article de Anglais | MEDLINE | ID: mdl-12717686

RÉSUMÉ

BACKGROUND: Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear. METHODS: Seven hundred and eighty-three newly diagnosed AML patients treated in the German SHG-AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission-rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers. RESULTS: With a median follow-up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox-regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients

Sujet(s)
Immunophénotypage/méthodes , Leucémie myéloïde/mortalité , Leucémie myéloïde/anatomopathologie , Maladie aigüe , Adolescent , Adulte , Sujet âgé , Antibiotiques antinéoplasiques/administration et posologie , Antimétabolites antinéoplasiques/administration et posologie , Cytarabine/administration et posologie , Daunorubicine/administration et posologie , Femelle , Humains , Leucémie myéloïde/traitement médicamenteux , Mâle , Adulte d'âge moyen , Analyse multifactorielle , Valeur prédictive des tests , Pronostic , Études rétrospectives , Facteurs de risque , Analyse de survie
18.
Ann Hematol ; 81(6): 343-6, 2002 Jun.
Article de Anglais | MEDLINE | ID: mdl-12107567

RÉSUMÉ

The risk of severe hepatic damage due to reactivation of hepatitis B virus (HBV) infection after intensive myelosuppressive chemotherapy is well known. Two of the most evolved nucleotide analogues showing good activity against the hepatitis B virus are lamivudine and famciclovir. We report the successful therapeutic use of lamivudine and famciclovir for fulminant reactivated hepatitis B after autologous peripheral blood stem cell transplantation (PBSCT) and the subsequent prophylactic use of lamivudine during allogeneic blood stem cell transplantation (alloSCT) for chronic lymphocytic leukemia (CLL) in a 40-year-old patient. Antiviral therapy was well tolerated and no hematotoxicity occurred. Our observation warrants further investigation of antiviral therapy with famciclovir and lamivudine in HBV carriers receiving intensive myelosuppressive chemotherapy.


Sujet(s)
Amino-2 purine/analogues et dérivés , Antiviraux/usage thérapeutique , Transplantation de cellules souches hématopoïétiques , Virus de l'hépatite B/croissance et développement , Hépatite B/traitement médicamenteux , Hépatite B/prévention et contrôle , Amino-2 purine/usage thérapeutique , Adulte , Famciclovir , Femelle , Humains , Lamivudine/usage thérapeutique , Transplantation autologue , Transplantation homologue , Activation virale
19.
Cancer Res ; 61(20): 7635-41, 2001 Oct 15.
Article de Anglais | MEDLINE | ID: mdl-11606405

RÉSUMÉ

The p53/Mdm2 pathway plays an important role in the induction of cell cycle arrest or apoptosis in response to genotoxic stress. Both the oncogene Bcr-Abl and physiological growth factors such as interleukin (IL)-3 can modulate the outcome of cellular exposure to DNA damage. To determine whether Bcr-Abl and growth factors can affect the p53/Mdm2 pathway, we studied the expression of Mdm2 in the IL-3-dependent pre-B cell line BaF3 and its bcr-abl-transfected derivative BaF3p185 after IL-3 deprivation or treatment with the c-Abl tyrosine kinase inhibitor STI571. We found that both growth factor withdrawal and inhibition of Bcr-Abl kinase lead to a down-regulation of Mdm2 preceding the induction of apoptosis. Apoptotic cell death induced by STI571 is partially dependent on p53. The early decrease of Mdm2 protein was not attributable to transcriptional regulation or to caspase-mediated cleavage. On the other hand, it could be completely blocked by the proteasomal inhibitor lactacystin. Targeted down-regulation of Mdm2 protein by antisense oligodeoxynucleotides overcame the survival effects of IL-3 and Bcr-Abl and resulted in accelerated apoptosis. Taken together, survival signals provided either by physiological growth factors or by oncogenic Bcr-Abl can positively regulate Mdm2, whereas Mdm2 ablation can reduce cell survival. These findings imply that, similarly to physiological growth factors such as IL-3, Bcr-Abl can promote cell survival through modulating the p53-Mdm2 pathway.


Sujet(s)
Lymphocytes B/physiologie , Régulation négative/effets des médicaments et des substances chimiques , Protéines de fusion bcr-abl/physiologie , Interleukine-3/physiologie , Mégacaryocytes/physiologie , Protéines nucléaires , Protéines proto-oncogènes/physiologie , Apoptose/effets des médicaments et des substances chimiques , Apoptose/physiologie , Lymphocytes B/effets des médicaments et des substances chimiques , Lymphocytes B/métabolisme , Benzamides , Lignée cellulaire , Survie cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/physiologie , Cysteine endopeptidases/métabolisme , Antienzymes/pharmacologie , Protéines de fusion bcr-abl/génétique , Humains , Mésilate d'imatinib , Interleukine-3/pharmacologie , Leucémie myéloïde chronique BCR-ABL positive/génétique , Mégacaryocytes/effets des médicaments et des substances chimiques , Mégacaryocytes/métabolisme , Mitogen-Activated Protein Kinases/métabolisme , Complexes multienzymatiques/métabolisme , Oligonucléotides antisens/pharmacologie , Pipérazines/pharmacologie , Proteasome endopeptidase complex , Protéines proto-oncogènes/biosynthèse , Protéines proto-oncogènes/génétique , Protéines proto-oncogènes c-abl/antagonistes et inhibiteurs , Protéines proto-oncogènes c-mdm2 , Pyrimidines/pharmacologie , Transfection
20.
Blood ; 98(5): 1532-41, 2001 Sep 01.
Article de Anglais | MEDLINE | ID: mdl-11520804

RÉSUMÉ

The phenotype of Bcr-Abl-transformed cells is characterized by a growth factor-independent survival and a reduced susceptibility to apoptosis. Furthermore, Bcr-Abl kinase alters adhesion features by phosphorylating cytoskeletal and/or signaling proteins important for integrin function. Integrin-mediated adhesion to extracellular matrix molecules is critical for the regulation of growth and apoptosis. However, effects of integrin signaling on regulation of apoptosis in cells expressing Bcr-Abl are largely unknown. The influence of adhesion on survival and apoptosis in Bcr-Abl+ and Bcr-Abl- BaF3 cells was investigated. p185bcr-abl-transfected BaF3 cells preadhered to immobilized fibronectin had a significant survival advantage and reduced susceptibility to apoptosis following gamma-irradiation when compared with the same cells grown on laminin, on polylysin, or in suspension. Both inhibition of Bcr-Abl kinase by STI571 and inhibition of specific adhesion reversed the fibronectin-mediated antiapoptotic effect in BaF3p185. The DNA damage response of Bcr-Abl- BaF3 cells was not affected by adhesion to fibronectin. In contrast to parental BaF3 cells, BaF3p185 adherent to fibronectin did not release cytochrome c to the cytosol following irradiation. The fibronectin-mediated antiapoptotic mechanism in Bcr-Abl-active cells was not mediated by overexpression of Bcl-XL or Bcl-2 but required an active phosphatidylinositol 3-kinase (PI-3K). Kinase-active Bcr-Abl in combination with fibronectin-induced integrin signaling led to a hyperphosphorylation of AKT. Thus, cooperative activation of PI-3K/AKT by Bcr-Abl and integrins causes synergistic protection of Bcr-Abl+ cells from DNA damage-induced apoptosis.


Sujet(s)
Apoptose/physiologie , Adhérence cellulaire/physiologie , Altération de l'ADN , Fibronectines/composition chimique , Protéines de fusion bcr-abl/physiologie , Protein-Serine-Threonine Kinases , Animaux , Apoptose/effets des radiations , Benzamides , Cycle cellulaire , Division cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire , Lignée de cellules transformées , ADN/effets des radiations , Activation enzymatique , Antienzymes/pharmacologie , Protéines de fusion bcr-abl/antagonistes et inhibiteurs , Rayons gamma , Régulation de l'expression des gènes , Mésilate d'imatinib , Méthode TUNEL , Intégrines/antagonistes et inhibiteurs , Intégrines/métabolisme , Interleukine-3/pharmacologie , Lymphocytes/effets des médicaments et des substances chimiques , Lymphocytes/métabolisme , Lymphocytes/effets des radiations , Souris , Microscopie confocale , Mitochondries/enzymologie , Pipérazines/pharmacologie , Protéines proto-oncogènes/métabolisme , Protéines proto-oncogènes c-akt , Protéines proto-oncogènes c-bcl-2/biosynthèse , Protéines proto-oncogènes c-bcl-2/génétique , Pyrimidines/pharmacologie , Protéines de fusion recombinantes/antagonistes et inhibiteurs , Protéines de fusion recombinantes/physiologie , Transfection , Protéine bcl-X
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