109 results on '"Eckhart Weidmann"'
Search Results
52. LUD 00-009: phase 1 study of intensive course immunization with NY-ESO-1 peptides in HLA-A2 positive patients with NY-ESO-1-expressing cancer
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Armin, Bender, Julia, Karbach, Antje, Neumann, Dirk, Jäger, Salah E, Al-Batran, Akin, Atmaca, Eckhart, Weidmann, Melina, Biskamp, Sacha, Gnjatic, Linda, Pan, Eric, Hoffman, Lloyd J, Old, Alexander, Knuth, and Elke, Jäger
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Adult ,Male ,Adolescent ,Granulocyte-Macrophage Colony-Stimulating Factor ,Membrane Proteins ,CD8-Positive T-Lymphocytes ,Middle Aged ,Cancer Vaccines ,Peptide Fragments ,Article ,Neoplasm Proteins ,Cohort Studies ,Treatment Outcome ,Antigens, Neoplasm ,Lymphatic Metastasis ,Neoplasms ,HLA-A2 Antigen ,Humans ,Female ,Hypersensitivity, Delayed ,Immunization ,Immunotherapy ,Aged ,T-Lymphocytes, Cytotoxic - Abstract
NY-ESO-1 is a cancer-testis antigen and an attractive target for immunotherapy in patients with different malignancies. Here we report the results of a phase I clinical study of intensive course NY-ESO-1 peptide vaccination, evaluating the safety, immunogenicity and clinical response in HLA-A2 positive patients with NY-ESO-1 expressing cancers. Of 20 patients enrolled in the trial, 14 completed at least 2 cycles of immunization and were evaluable for clinical and immunological response. Five of these evaluable patients were treated in cohort 1 (baseline seropositive) and 9 patients were treated in cohort 2 (baseline seronegative). During vaccination, NY-ESO-1-specific CD8+ T-cells were induced in 3 of 9 baseline seronegative patients. In patients with pre-existing antigen-specific CD8+ T-cells, their number increased or remained stable. In contrast to previous immunization protocols with less intensive immunization schedules, we observed a rapid induction of high magnitude NY-ESO-1 peptide-specific T-cell responses detectable already on day 15-22 of immunization. A specific immune response of high magnitude and early onset may be more effective in eliminating minimal residual disease in adjuvant treatment situations and in preventing tumor progression due to immune escape mechanisms.
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- 2007
53. Dexa-BEAM as salvage therapy in patients with primary refractory aggressive non-Hodgkin lymphoma
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Hans Martin, Paris S. Mitrou, Eckhart Weidmann, Johannes Atta, Dieter Hoelzer, and Kai U Chow
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Salvage therapy ,Aggressive Non-Hodgkin Lymphoma ,CHOP ,Transplantation, Autologous ,Dexamethasone ,Autologous stem-cell transplantation ,Refractory ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,In patient ,Melphalan ,Etoposide ,Salvage Therapy ,business.industry ,Lymphoma, Non-Hodgkin ,Remission Induction ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Carmustine ,Combined Modality Therapy ,Hematopoietic Stem Cell Mobilization ,Surgery ,Transplantation ,Survival Rate ,Oncology ,Female ,Stem cell ,Neoplasm Recurrence, Local ,business - Abstract
Although aggressive NHL in relapse after remission can still be cured by second-line treatment followed by high-dose therapy and autologous stem cell transplantation, the long-term prognosis of patients who fail to obtain remission after first-line therapy remains extremely poor. We retrospectively evaluated a series of 29 consecutive patients with primary refractory high-grade NHL who were treated with Dexa-BEAM (DB) as uniform salvage therapy at a single institution. Twenty-nine patients with aggressive NHL primary refractory to CHOP or CHOP-like induction therapy with a median age of 47 (range, 22 - 64) years received 1 - 2 cycles of DB and were candidates for subsequent autologous stem cell (PBSC) mobilization and transplantation (PBSCT). Follow-up of all patients was updated in March 2004. Eight of 29 patients (28%) responded to one cycle of DB (1 complete/7 partial remissions); 2 of whom are alive after PBSCT (1 autologous/1 matched unrelated donor), 1 patient died after autologous PBSCT. Reasons for failure to proceed to high-dose therapy in spite of response to DB were recurrent progressive disease (n = 2), septicemia (n = 1), and allogeneic transplant-related mortality after mobilization failure to DB (n = 2). Twenty-one patients failed to respond to DB and died of progressive disease. Overall survival was 7% after 41 months. We conclude that Dexa-BEAM salvage therapy is not effective in patients with truly primary refractory high-grade NHL. The efficiency of rituximab combined with Dexa-BEAM or novel chemotherapeutic strategies needs to be established.
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- 2007
54. Mitomycin C, 5-fluorouracil, leucovorin, and oxaliplatin as a salvage therapy for patients with cisplatin-resistant advanced gastric cancer: a phase I dose escalation trial
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Yvonne Kolassa, Antje Neumann, Eckhart Weidmann, Claudius Dechow, Salah-Eddin Al-Batran, Elke Jäger, Joerg T. Hartmann, Sebastian Schmidt, Anne Kerber, Akin Atmaca, and Ernst Reitsamer
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Organoplatinum Compounds ,Mitomycin ,Leucovorin ,Salvage therapy ,Antineoplastic Agents ,Stomach Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Dose escalation ,Humans ,heterocyclic compounds ,neoplasms ,Aged ,Salvage Therapy ,Terminal Care ,Dose-Response Relationship, Drug ,business.industry ,Mitomycin C ,Hematology ,Advanced gastric cancer ,Middle Aged ,Hematologic Diseases ,digestive system diseases ,Oxaliplatin ,stomatognathic diseases ,Treatment Outcome ,Fluorouracil ,Drug Resistance, Neoplasm ,Toxicity ,Cisplatin resistant ,Feasibility Studies ,Female ,Cisplatin ,business ,therapeutics ,medicine.drug - Abstract
This study aimed at evaluating the feasibility and toxicity of a salvage therapy with mitomycin C (MMC), 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with cisplatin-resistant advanced gastric cancer.A 3-patient cohort dose-escalating study design was used. The patients received FLO: oxaliplatin 85 mg/m2, 5-FU 2,600 mg/m2 (24 h), leucovorin 200 mg/m2 on days 1, 15, and 29 plus MMC on day 1 (FLOM). The MMC dose was escalated from 6 to 12 mg/m2 in 2- mg/m2 steps. Cycles were repeated every 6 weeks.Twenty patients were enrolled in 4 treatment cohorts. The treatment was well tolerated with grade 3 or 4 nonhematological toxicities affecting less than 5% of patients. Grade 3 or 4 neutropenia, anemia, and thrombocytopenia were observed in 9 (45%), 7 (35%), and 5 (25%) of 20 patients, respectively. Mild but prolonged thrombocytopenia was dose limiting, requiring treatment discontinuation or a treatment delayor=2 weeks in 8 (40%) of 20 patients. MMC 10 mg/m2 every 6 weeks was considered as the optimal dose in combination with FLO. Objective responses were observed in 7 (35%) of 20 patients, and 7 further patients (35%) had stable disease. Median time to progression and overall survival were 4.1 and 8 months, respectively.Prolonged cumulative myelotoxicity was dose limiting in the therapy with MMC, 5-FU, and oxaliplatin. This combination chemotherapy seems to overcome cisplatin resistance in patients with advanced gastric cancer.
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- 2007
55. Common features and differences in the transcriptome of large cell anaplastic lymphoma and classical Hodgkin's lymphoma
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Klaus, Willenbrock, Ralf, Küppers, Christoph, Renné, Verena, Brune, Susan, Eckerle, Eckhart, Weidmann, Andreas, Bräuninger, and Martin-Leo, Hansmann
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Adult ,B-Lymphocytes ,Leukemia ,Lymphoma ,Transcription, Genetic ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Hodgkin Disease ,Neoplasm Proteins ,RNA, Complementary ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Cell Line, Tumor ,Humans ,Lymphoma, Large-Cell, Anaplastic ,Female ,RNA, Messenger ,RNA, Neoplasm ,Oligonucleotide Array Sequence Analysis - Abstract
Anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (HL) are derived from different cell types, namely T cells and B cells, respectively. However, both lymphomas share a similar cytological and immunohistochemical tumor cell phenotype with little resemblance to their cells of origin.In this study, the transcriptional profiles of ALCL cell lines, primary ALCL tumor cells from peripheral blood and HL cell lines were compared to each other and to normal B-cell subsets, B non-Hodgkin's lymphomas (NHL) and B NHL- and Epstein-Barr virus (EBV)-transformed B-cell lines in order to establish their relationship at the transcriptional level and to identify genes with possible pathobiological impact. Expression of some of the genes identified was confirmed in microdissected primary tumor cells by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry.HL samples clustered separately from ALCL samples, but HL and ALCL were found to be more closely related to each other than to any normal or malignant B-cell sample in the dataset. Their relationship was determined to a large extent, but not exclusively, by lack of expression of B-cell antigens and by the over-expression of mRNA encoding activation markers and structural proteins. Apart from established differences between HL and ALCL, further genes of interest could be identified that distinguish both entities from each other and from the other samples. The differential expression of PRAME, DDR2, SOCS3 and CEBPD in HL and ALCL was confirmed in primary tumor tissue by immunohistochemistry and/or RT-PCR.At a transcriptional level HL is more closely related to Alk+ ALCL than to the B-NHL or B-cell samples investigated, although it is a B-cell derived lymphoma. The newly identified genes discriminating HL and ALCL may be pathobiologically important and may serve as possible therapeutic targets.
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- 2006
56. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study
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Jürgen Barth, Alexander Burchardt, Wolfgang Blau, Georg Maschmeyer, Ulrich von Grünhagen, Martina Stauch, Andrea Heider, Arnold Ganser, Wolfram Brugger, Hans Peter Böck, Gerhard Heil, Eckhart Weidmann, Frank Kauff, Christoph Losem, Heinz Dürk, Axel Hinke, Ulrich Kaiser, Manfred Welslau, Christina Balser, and Mathias J. Rummel
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Bendamustine ,medicine.medical_specialty ,business.industry ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,CHOP ,Biochemistry ,Gastroenterology ,Confidence interval ,Surgery ,Internal medicine ,medicine ,Clinical endpoint ,In patient ,Rituximab ,business ,Survival rate ,medicine.drug - Abstract
Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or MCL and was presented at ASH 2009, ASCO 2012, and published in The Lancet in 2013. The final published analysis at a median follow-up of 45 months demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group, compared to the CHOP-R group (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.44–0.74; p Methods: 549 pts with indolent lymphomas or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: 514 randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. Fewer pts treated initially with B-R needed second-line treatments due to disease progression compared to CHOP-R treated pts: 93 pts (36%) in the B-R group received salvage treatment compared with 140 pts (55%) in the CHOP-R group. Of those in the CHOP-R group, 69 pts (49%) received B-R as salvage. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.53, 95% CI 0.40-0.68; p The difference in complete response (CR) rates (independent of treatment arms) between male (n=272, median age 63 years) and female (n=242, median age 64 years) pts was statistically significant: 28.6% for male pts versus 42.1% for female pts (p=0.0016). Female pts had a longer median TTNT compared to male pts (not yet reached vs. 52.2 months, respectively; HR 0.70, 95% CI 0.54-0.90; p=0.006). The achievement of a CR was associated with significantly prolonged OS, with an estimated 10-year survival rate of 72.6% for pts with a CR and 63.6% for pts with a partial response (p=0.006). The difference in OS between the treatment arms was not statistically significant, with 65 and 76 deaths in the B-R and CHOP-R arms, respectively. The estimated 10-year survival rates were 67.4% for B-R and 60.1% for CHOP-R (p=0.262). In pts with indolent lymphomas (total group without MCL), there was a trend toward longer survival for the B-R group compared with the CHOP-R group, with 43 deaths out of 215 pts (20.0%) in B-R and 58 deaths out of 205 pts (28.3%) in CHOP-R. The estimated 10-year survival rates for pts with indolent lymphomas were 71.9% for B-R and 61.5% for CHOP-R (HR 0.70, 95% CI 0.48-1.04; p=0.076). No difference in OS was found in the subgroup of pts with MCL (n=95) (HR 1.28, 95% CI 0.69-2.39; p=0.429). Twenty sNPL were observed in the B-R group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R) to date. Updated sNPL results will be presented at the ASH meeting. Conclusions: In pts with previously untreated indolent lymphomas, and in elderly pts with MCL, B-R demonstrates a PFS and TTNT benefit over CHOP-R. OS for the entire group of patients was not significantly different while treatment with B-R resulted in a trend toward survival benefit in the group of pts with indolent lymphomas. Disclosures Off Label Use: Indication and dosage of bendamustine.
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- 2014
57. Bendamustine Plus Rituximab Versus Fludarabine Plus Rituximab in Patients with Relapsed Follicular, Indolent, or Mantle Cell Lymphomas – 8-Year Follow-up Results of the Randomized Phase III Study NHL 2-2003 on Behalf of the StiL (Study Group Indolent Lymphomas, Germany)
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Mathias J. Rummel, Christina Balser, Ulrich Kaiser, Hans Peter Böck, Martina Beate Stauch, Andrea Heider, Manfred Welslau, Christoph Losem, Eckhart Weidmann, Wolfgang Blau, Alexander Burchardt, Jürgen Barth, Frank Kauff, Axel Hinke, and Wolfram Brugger
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction: Fludarabine plus rituximab (F-R) is an established treatment option for patients (pts) with relapsed/refractory follicular lymphoma (FL), other indolent lymphoma, or mantle cell lymphoma (MCL). To further improve the treatment in this setting we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of bendamustine plus rituximab (B-R) versus F-R for pts with relapsed FL, other indolent lymphomas or MCL. Patients and Methods: 230 pts in need of treatment were randomized to rituximab 375 mg/m² (day 1) plus either bendamustine 90 mg/m² (days 1+2) or fludarabine 25 mg/m² (days 1–3) q 28 days for a maximum of 6 cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended; however, in case of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and complete response rate (CR). The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 q 3 months for up to 2 years) in both arms, following regulatory approvals in this setting. Results: A total of 219 pts were evaluable for the analysis (114 B-R; 105 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration, and extranodal involvement. Most pts had stage IV (71.6% B-R; 60.6% F-R) or stage III disease (21.1% B-R; 25.3% F-R). Median patient age was 68 yrs (range 38–87). Patients had received a median of 1 prior therapy (range 1–7). Histological subtypes were distributed equally between the B-R and F-R arms: follicular, 45.9% and 47.5%, respectively; Waldenström’s Macroglobulinemia, 11.9% and 11.1%; MCL, 20.2% and 21.2%; other indolent lymphomas, 23% and 20.2%. A median of 6 cycles were given in both treatment arms, with 75.2% and 53.4% of B-R and F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2014), the median observation time was 96 months. The ORR was significantly higher with B-R than with F-R (83.5% vs. 52.5%, respectively; p< 0.0001). The CR rate with B-R was also significantly higher than that with F-R (38.5% vs. 16.2%; p=0.0004). Median PFS was significantly prolonged with B-R compared with F-R (34 vs. 12 months; hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.38–0.72; p There were no significant differences in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy, or infectious episodes between groups. Hematologic toxicities were also similar between arms: 8.9% grade 3/4 neutropenia with B-R vs. 9.1% with F-R; 11.8% grade 3/4 leukocytopenia with B-R vs. 12.4% with F-R. The overall incidence of serious adverse events was similar for the B-R and F-R groups (17.4% and 22.2%, respectively). 17 pts (14.9%) developed a secondary neoplasia after B-R compared with 16 pts (15.2%) after F-R. Of these, 5 pts in the B-R group, and 3 pts in the F-R group developed a secondary hematological neoplasia (2 AML [1 AML M4], 1 CML, 1 DLBCL, and 1 HD after B-R; and 2 AML M4, and 1 MDS after F-R). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.38, 95% CI 0.32-0.71; p=0.0003) and PFS (HR 0.35, 95% CI 0.31-0.62; p< 0.0001) in the small group of 40 pts who received this treatment (23 B-R, 17 F-R) compared with those who did not. Although the numbers are too small in this non-randomized comparison to draw validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: B-R was more effective than F-R in this setting of relapsed FL, other indolent lymphomas and MCL due to higher overall and complete response rates, a longer PFS, and an improved OS. These data confirm the high anti-lymphoma activity of B-R. Disclosures Off Label Use: Indication and dosage of bendamustine.
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- 2014
58. In vivo drug-response in patients with leukemic non-Hodgkin's lymphomas is associated with in vitro chemosensitivity and gene expression profiling
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Daniel Nowak, Eckhart Weidmann, Paris S. Mitrou, Wolf-Karsten Hofmann, Bernd Schneider, Martina Komor, Soo-Zin Kim, Dieter Hoelzer, Kai Uwe Chow, and Simone Boehrer
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Programmed cell death ,Adenosine ,Cell Culture Techniques ,Antineoplastic Agents ,Apoptosis ,Biology ,Antibodies, Monoclonal, Murine-Derived ,In vivo ,medicine ,Leukocytes ,Humans ,Epirubicin ,Oligonucleotide Array Sequence Analysis ,Pharmacology ,Clusterin ,Gene Expression Profiling ,Lymphoma, Non-Hodgkin ,Antibodies, Monoclonal ,Cell cycle ,medicine.disease ,Molecular biology ,Lymphoma ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,Nitrogen Mustard Compounds ,Cancer research ,biology.protein ,Rituximab ,Chemosensitivity assay - Abstract
Only a few approaches are available to address the mechanisms of cell death in vivo which are induced by anticancer treatment in patients with malignancies. In this study in vitro chemosensitivity testing of primary peripheral blood leukemic cells of five patients suffering from different leukemic non-Hodgkin's lymphomas was combined with the analysis of the in vivo rate of apoptosis by flow-cytometry (Annexin V and depolarisation of mitochondrial membrane potential (MMP) by JC-1). Furthermore, changes in expression patterns of apoptosis related proteins during chemotherapeutic treatment were detected by Western Blot. Gene expression profiling (HG-U133A, Affymetrix, Santa Clara, CA) was employed to identify common marker genes of in vivo drug response. In vitro chemosensitivity was tested using the cytotoxic agents which the patients were scheduled to receive and was strongly correlated with effective reduction of leukemic lymphoma cells in patients resulting in complete remissions in all five cases. Due to the rapid clearance of apoptotic tumor cells in vivo neither the analysis of the in vivo rate of apoptosis and depolarisation of MMP nor the assessment of expression of regulators of apoptosis showed concordant results concerning the drug response. However, assessment of gene expression during therapy could identify a set of 30 genes to significantly discriminate between samples from patients before treatment compared to samples from the same patients after receiving cytotoxic therapy. Among these 30 genes we found a high proportion of genes associated with apoptotic cell death, cell proliferation and cell cycle signalling including complement lysis inhibitor (clusterin/CLU), beta-catenin interacting protein (ICAT), peroxisome proliferator activated receptor alpha (PPARα), TNF alpha converting enzyme (ADAM17/TACE), homeo box A3 (HOX1), inositol polyphosphatase 5-phosphatase type IV (PPI5PIV) and inhibitor of p53 induced apoptosis alpha (IPIA-Alpha/NM23-H6). These results indicate that in vitro chemosensitivity testing and gene expression profiling can successfully be utilised to analyse in vivo drug response in patients with leukemic NHL's and can be used to explore new pathway models of drug-induced cell death in vivo which are independent of different lymphoma subtypes and different treatment regimens.
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- 2005
59. Upon drug-induced apoptosis expression of prostate-apoptosis-response-gene-4 promotes cleavage of caspase-8, bid and mitochondrial release of cytochrome c
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Natasa Kukoc-Zivojnov, Paris S. Mitrou, Daniel Nowak, Simone Boehrer, Elena Puccetti, Marion Bergmann, Eckhart Weidmann, Dieter Hoelzer, Christine Baum, and Kai Uwe Chow
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Apoptosis ,Mitochondrion ,Caspase 8 ,Jurkat Cells ,Survivin ,Humans ,Receptor ,Antibiotics, Antineoplastic ,biology ,Gene Expression Regulation, Leukemic ,Cytochrome c ,Intracellular Signaling Peptides and Proteins ,Cytochromes c ,Hematology ,Cell biology ,Mitochondria ,Cytosol ,Protein Transport ,Doxorubicin ,Caspases ,biology.protein ,Apoptosome ,Apoptosis Regulatory Proteins ,Carrier Proteins ,BH3 Interacting Domain Death Agonist Protein ,Signal Transduction - Abstract
Par-4 functions as a tumor suppressor antagonizing the transforming capacity and the resistance of malignant cells towards apoptotic stimuli. After demonstrating that par-4 promotes apoptosis by activating signaling of the intrinsic pathway of apoptosis, we hypothesized that par-4 also impacts on key molecules of the extrinsic pathway without the requirement of a receptor/ligand interaction. Here, we provide first evidence, that expression of par-4 increases cleavage of caspase-8, truncation of Bid and its translocation to the mitochondria, resulting in an augmentation of cytochrome c and AIF efflux into the cytosol, effects par-4-positive cells are able to retain to a higher extent than par-4-negative cells upon inhibition of caspase-3 activation.
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- 2005
60. In malignant myeloid cells expression of Daxx downregulates expression of p53 and of the inhibitors of apoptosis proteins
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Eckhart Weidmann, Angela Brieger, Marion Bergmann, Paris S. Mitrou, Simone Schaaf, Kai Uwe Chow, Dieter Hoelzer, Daniel Nowak, and Simone Boehrer
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Genetic Vectors ,Down-Regulation ,Caspase 8 ,Inhibitor of apoptosis ,Transfection ,Caspase 7 ,Culture Media, Serum-Free ,Inhibitor of Apoptosis Proteins ,Death-associated protein 6 ,Bcl-2-associated X protein ,Cell Line, Tumor ,Survivin ,Humans ,Caspase 10 ,Promoter Regions, Genetic ,Caspase ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,bcl-2-Associated X Protein ,Regulation of gene expression ,Enzyme Precursors ,biology ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Proteins ,Hematology ,Cell biology ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-bcl-2 ,Caspases ,biology.protein ,Leukemia, Erythroblastic, Acute ,Tumor Suppressor Protein p53 ,Carrier Proteins ,Co-Repressor Proteins ,Molecular Chaperones - Abstract
The role of Daxx, in particular its ability to promote or hinder proliferation, still remains controversial. In order to elucidate the functional relevance of Daxx in malignant myelocytes, the erythroleukemia cell line HEL was stably transfected with a Daxx-expressing vector or with the respective Daxx-negative control vector. Assessing the molecular consequences of ectopic Daxx-expression, we present evidence that Daxx downregulates p53. Moreover, we demonstrate that Daxx overexpressing myelocytes downregulate the proapoptotic Bcl-2 family member Bax, while expression of antiapoptotic Bcl-2 is not influenced. Furthermore, expression of Daxx diminishes expression levels of the initiator-procaspase-8 and -10, and the executioner procaspase-7, whereas the procaspase-3, -6 and -9 remain unaltered. The altered protein levels of the caspases in Daxx overexpressing myelocytes are accompanied by a decrease of expression levels of the inhibitor of apoptosis proteins (IAPs) cIAP-1, -2 and survivin. Despite the described impact of Daxx expression on major molecules of the apoptotic cascade, expression of Daxx in neoplastic myelocytes does not impact on the rate of proliferation. Upon a proapoptotic stimulus such as serum withdrawal Daxx is unable to maintain its influence on expression levels of p53, Bax, IAPs and the procaspase-8, -10 and -7.
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- 2004
61. Expression of Daxx sensitizes Jurkat T-cells to the apoptosis-inducing effect of chemotherapeutic agents
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Kai Uwe Chow, Eckhart Weidmann, Soo-Zin Kim, Paris S. Mitrou, Dieter Hoelzer, Simone Boehrer, Simone Hochmuth, Daniel Nowak, and Natasa Kukoc-Zivojnov
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Pharmacology ,Co-Repressor Proteins ,T-Lymphocytes ,Intracellular Signaling Peptides and Proteins ,Signal transducing adaptor protein ,Nuclear Proteins ,Antineoplastic Agents ,Apoptosis ,Transfection ,Biology ,Jurkat cells ,Cell biology ,XIAP ,Jurkat Cells ,Death-associated protein 6 ,Gene Expression Regulation ,Survivin ,Humans ,Carrier Proteins ,Adaptor Proteins, Signal Transducing ,Molecular Chaperones - Abstract
Background: The role of Daxx, in particular its ability to promote or hinder apoptosis, still remains controversial. In order to elucidate the functional relevance of Daxx in the extrinsic signaling of malignant lymphocytes Jurkat T-cells were stably transfected with a Daxx-expressing vector or with the respective Daxx-negative control vector. Results: Assessing first the impact of Daxx expression on the rate of proliferation we demonstrate that overexpression of Daxx alone is not sufficient to alter proliferation in neoplastic lymphocytes. Nevertheless, expression of Daxx down-regulates anti-apoptotic Bcl-2 and up-regulates pro-apoptotic BID. In addition, Daxx-overexpressing Jurkat cells exhibit a decreased expression of the pro-caspase-8, -10, -9 and -3 and a concomitant increase of the inhibitors of apoptosis proteins survivin, XIAP, cIAP-1 and -2. We further demonstrate, that upon incubation with various chemotherapeutic agents these Daxx-induced molecular alterations sensitize Jurkat T-cells to the apoptosis-inducing effects of specific chemotherapeutic agents. Conclusions: We here outline the molecular changes elicited by Daxx on major components of the apoptotic cascade of malignant lymphocytes and demonstrate the capacity of Daxx to sensitize these cells to the apoptosis-inducing effect of various chemotherapeutic agents.
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- 2004
62. Expression of ZAP-70 protein correlates with disease stage in chronic lymphocytic leukemia and is associated with, but not generally restricted to, non-mutated Ig VH status
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Simone Boehrer, Lana Harder, Eckhart Weidmann, Natasa Kukoc-Zivojnov, Soo-Zin Kim, Susanne Annette Steimle-Grauer, Dieter Hoelzer, Paris Sophokles Mitrou, Kai Uwe Chow, and Angela Brieger
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Adult ,Male ,Cancer Research ,Chronic lymphocytic leukemia ,Immunoglobulin Variable Region ,chemical and pharmacologic phenomena ,Disease ,CD38 ,Biology ,medicine.disease_cause ,medicine ,Humans ,Gene ,Survival analysis ,Aged ,Neoplasm Staging ,Mutation ,B-Lymphocytes ,ZAP-70 Protein-Tyrosine Kinase ,Genes, Immunoglobulin ,hemic and immune systems ,Hematology ,Sequence Analysis, DNA ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,Molecular biology ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Analysis ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Oncology ,Immunology ,Disease Progression ,Immunoglobulin heavy chain ,Female ,Immunoglobulin Heavy Chains ,Tyrosine kinase - Abstract
The mutational status of immunoglobulin variable region genes (Ig VH) is a well established prognostic parameter in chronic lymphocytic leukemia (CLL). Recently, a subset of genes with a characteristic expression profile correlating with the mutational status of B-CLLs has been identified. One of the overexpressed genes in the prognostically unfavorable group of CLL patients with unmutated Ig VH genes encodes for the protein tyrosine kinase ZAP-70, which is physiologically involved in T-cell signaling. Since ZAP-70 has been described to be prognostically relevant in CLL, we analyzed the possible relationship of its expression to the mutational status of Ig VH genes as well as to other prognostic factors in CLL and indolent lymphomas. The mutational status of Ig VH genes was analyzed by seminested PCR, direct sequencing and comparison with the sequences of the EMBL databases in 60 samples of patients with B-CLL and 18 samples of patients with indolent B-cell malignancies. ZAP-70 protein expression was assessed in all samples by immunoblotting and for semiquantitative analysis the ratio of ZAP-70 to tubulin expression was calculated. ZAP-70 protein was found to be expressed in all investigated B-cell malignancies. Expression levels varied within a wide range in each entity. The highest mean level of ZAP-70 expression was observed in unmutated B-CLLs, however, with broad expression variability. High levels of ZAP-70 expression correlated with higher stage Binet B or C and with unmutated Ig VH genes. Overall survival rates estimated by Kaplan-Meier curves did not differ among patients with high or low ZAP-70 expression. We conclude that ZAP-70 is associated with the mutational status of Ig VH genes, but this expression pattern is not present in all individual cases. Furthermore, high levels of ZAP-70 correlated with Binet stages B or C indicating an involvement of ZAP-70 in mechanisms promoting growth of B-CLL cells.
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- 2004
63. In the erythroleukemic cell line HEL Prostate-apoptosis-response-gene-4 (par-4) fails to down-regulate Bcl-2 and to promote apoptosis
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Eckhart Weidmann, Kai Uwe Chow, Martin Ruthardt, Daniel Nowak, Simone Boehrer, Natasa Kukoc-Zivojnov, Simone Schaaf, Angela Brieger, Dieter Hoelzer, and Paris S. Mitrou
- Subjects
Cancer Research ,Apoptosis ,Signal transduction inhibitor ,Hydroxamic Acids ,Piperazines ,TNF-Related Apoptosis-Inducing Ligand ,Caspase 10 ,bcl-2-Associated X Protein ,Caspase 8 ,Enzyme Precursors ,Membrane Glycoproteins ,Gene Expression Regulation, Leukemic ,Intracellular Signaling Peptides and Proteins ,Antibodies, Monoclonal ,Nuclear Proteins ,Hematology ,Caspase 9 ,Cell biology ,Neoplasm Proteins ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,Caspases ,Benzamides ,Imatinib Mesylate ,Co-Repressor Proteins ,medicine.drug ,Cell type ,Antineoplastic Agents ,Biology ,Transfection ,Death-associated protein 6 ,Downregulation and upregulation ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Humans ,fas Receptor ,Adaptor Proteins, Signal Transducing ,Tumor Necrosis Factor-alpha ,Genes, bcl-2 ,Histone Deacetylase Inhibitors ,Trichostatin A ,Pyrimidines ,Cell culture ,Histone deacetylase ,Leukemia, Erythroblastic, Acute ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Molecular Chaperones - Abstract
In a variety of malignant cells Prostate-apoptosis-response-gene-4 (Par-4) exhibits a pro-apoptotic influence sensitizing these cells to apoptosis-inducing agents by downregulating expression of Bcl-2. Considering the crucial role of Bcl-2 in the development of chemoresistance of acute myeloid leukemia (AML) cells, we here assessed the potential of Par-4 to down-regulate Bcl-2 and to induce apoptosis in the erythroleukemic cell line HEL. Testing a potential pro-apoptotic role of Par-4 upon incubation with various conventional chemotherapeutic drugs, novel agents such as the signal transduction inhibitor STI 571 and the histone deacetylase (HDAC)- inhibitor trichostatin A (TSA), as well as with the experimental substances Fas and TRAIL, we provide evidence that in the erythroleukemic cell line HEL expression of Par-4 is not sufficient to sensitize to any of these pro-apoptotic stimuli. We further demonstrate that – in contrast to previous reports in non-AML cells - Par-4 expression in HEL cells leads to an upregulation of Bcl-2. Moreover, Par-4-positive HEL cells exhibit a decreased level of the proapoptotic protein Bax as compared to Par-4- negative cells. In addition, Par-4 increases the expression of Daxx – whose downregulation is associated with augmented chemosensitivity – as well as expression of the procaspases-8, -9 and -10, whereas the levels of the procaspases-3 and -7 remain unaltered. In conclusion we here demonstrate that in the erythroleukemic cell line HEL – in contrast to other cell types – Par-4 fails to promote apoptosis and outline the underlying molecular mechanisms.
- Published
- 2004
64. Upon drug-induced apoptosis in lymphoma cells X-linked inhibitor of apoptosis (XIAP) translocates from the cytosol to the nucleus
- Author
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Kai Uwe Chow, Paris S. Mitrou, Simone Schaaf, Dieter Hoelzer, Simone Boehrer, Eckhart Weidmann, Soo-Zin Kim, Angela Brieger, and Daniel Nowak
- Subjects
Cancer Research ,Programmed cell death ,Lymphoma, B-Cell ,Ubiquitin-Protein Ligases ,Intranuclear Inclusion Bodies ,Antineoplastic Agents ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Inhibitor of apoptosis ,Inhibitor of Apoptosis Proteins ,Cytosol ,Annexin ,Cell Line, Tumor ,Humans ,Caspase ,Cell Nucleus ,B-Lymphocytes ,biology ,Dose-Response Relationship, Drug ,Proteins ,Hematology ,Subcellular localization ,Flow Cytometry ,XIAP ,Cell Compartmentation ,Mitochondria ,Neoplasm Proteins ,Protein Transport ,Oncology ,HtrA serine peptidase 2 ,Microscopy, Fluorescence ,Cancer research ,biology.protein - Abstract
The X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis-1 (cIAP-1) are emerging as versatile proteins in programmed cell death with a scope of possible functions reaching far beyond their well known inhibitory effects on caspases. We previously demonstrated that the ability of drugs to modify expression and cleavage of the IAPs are crucial for the synergistic effects achieved by the combinations of different cytotoxic drugs employed to treat malignant lymphomas. In order to more clearly assess the underlying molecular mechanisms, we here evaluated the consequences of drug-induced apoptosis on the localization and aggregation of XIAP and cIAP-1. The influence of drug-induced apoptosis on localization of IAPs was investigated using immunofluorescence microscopy as well as western blot analysis. Apoptosis was induced by chemotherapeutic drugs with different modes of action (bendamustine, cladribine, fludarabine, doxorubicin and mitoxantrone) and assessed by flow-cytometry using Annexin V. We demonstrate that XIAP and cIAP-1 are downregulated and/or cleaved in a dose-dependent manner upon treatment with a variety of anti-cancer drugs. Moreover we provide evidence that in the context of drug-induced apoptosis XIAP, its BIR3-RING cleavage product and cIAP-1 undergo an extensive change of subcellular localization. Immunofluorescence microscopy reveals that XIAP, in contrast to cIAP-1, is located in discrete cytosolic protein aggregates and-upon induction of apoptosis with cytotoxic drugs--redistributes into large nuclear inclusions. This translocation of XIAP and its BIR3-RING cleavage product from the cytosol into the nucleus is confirmed by cell fractionation and western blot analyses. Of note, in this experimental setting putative interaction partners of XIAP-such as Apaf-1, caspase-3 and -7--do not co-localize with XIAP. These results imply a new unknown function of XIAP and its BIR3-RING fragment in the nucleus in the context of drug-induced apoptosis. The localization of cIAP-1 in mitochondria and its liberation from these indicate a profoundly different function of this protein despite its similar modular structure to XIAP.
- Published
- 2004
65. Daxx overexpression in T-lymphoblastic Jurkat cells enhances caspase-dependent death receptor- and drug-induced apoptosis in distinct ways
- Author
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Daniel Nowak, Soo-Zin Kim, Bettina Trepohl, Kai Uwe Chow, Simone Hochmuth, Dieter Hoelzer, Simone Boehrer, Eckhart Weidmann, Paris S. Mitrou, and Amina Afkir
- Subjects
Genetic Vectors ,Gene Expression ,Apoptosis ,Biology ,Inhibitor of apoptosis ,Lymphoma, T-Cell ,Transfection ,Jurkat cells ,Inhibitor of Apoptosis Proteins ,TNF-Related Apoptosis-Inducing Ligand ,Jurkat Cells ,Death-associated protein 6 ,Humans ,fas Receptor ,Membrane Glycoproteins ,Tumor Necrosis Factor-alpha ,Intrinsic apoptosis ,Intracellular Signaling Peptides and Proteins ,Proteins ,Cell Biology ,Fas receptor ,Cell biology ,XIAP ,Proto-Oncogene Proteins c-bcl-2 ,Doxorubicin ,Caspases ,Signal transduction ,Apoptosis Regulatory Proteins - Abstract
The role of Daxx, in particular, its ability to promote or hinder apoptosis, still remains controversial. In order to elucidate the functional relevance of Daxx in apoptosis signaling of malignant lymphocytes, Jurkat T-cells were stably transfected with a Daxx-expressing vector or with the respective Daxx-negative control vector. We thus demonstrate that ectopic expression of Daxx substantially increases the rate of apoptosis upon incubation with death receptor agonists such as Fas and TRAIL as well as upon incubation with the cytotoxic drug doxorubicin (DOX). Analysis of the molecular changes induced in the extrinsic and intrinsic apoptosis pathways reveals that augmentation of apoptosis by Daxx overexpression is conveyed by distinctly different mechanisms. Although enforced apoptosis caused by ectopic Daxx expression is caspase-dependent in both cases, major differences between Fas/TRAIL-induced apoptosis and doxorubicin-induced apoptosis are observed in expression patterns of X-linked inhibitor of apoptosis (XIAP), p53, Bid, ZIP kinase, and prostate apoptosis response gene 4 (Par-4). Moreover, we could show that addition of a CD95 blocking antibody to the clones treated with doxorubicin was able to increase apoptosis as compared to doxorubicin treatment alone and was accompanied by an enhancement of the mitochondrial branch of apoptosis. In conclusion, we here outline the major molecular mechanisms underlying the apoptosis-promoting effect of Daxx in neoplastic lymphocytes and demonstrate fundamental molecular differences elicited by the overexpression of Daxx in the extrinsic and intrinsic signaling pathways.
- Published
- 2004
66. Prostate apoptosis response gene-4 sensitizes neoplastic lymphocytes to CD95-induced apoptosis
- Author
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Marion Bergmann, Kai U Chow, Bettina Trepohl, Paris S. Mitrou, Simone Boehrer, Eckhart Weidmann, Dieter Hoelzer, and Natasa Kukoc-Zivojnov
- Subjects
Male ,Fas Ligand Protein ,Cell ,Apoptosis ,Caspase 8 ,Jurkat cells ,Jurkat Cells ,medicine ,Humans ,Lymphocytes ,fas Receptor ,Inhibitor of apoptosis domain ,Membrane Glycoproteins ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Prostate ,Hematology ,General Medicine ,Fas receptor ,XIAP ,Cell biology ,medicine.anatomical_structure ,Flip ,Cancer research ,Apoptosis Regulatory Proteins ,Carrier Proteins - Abstract
Evaluating the functional consequences of prostate apoptosis response gene-4 (par-4) expression in CD95-induced apoptosis of neoplastic lymphocytes, we demonstrate that par-4 increases apoptosis by upregulating the CD95 receptor on the cell surface and--with a concomitant decrease of the FLICE-like inhibitory protein (FLIP)--by promoting cleavage of the initiator caspases-8 and -10. This results in an enforced activation of the executioner caspases-6, -7, and -3 as well as in an activation of the mitochondrial pathway. Upon inhibition of caspase-8, overexpression of par-4 enables Jurkat cells to maintain a higher sensitivity to CD95-induced apoptosis by downregulating cIAP-2 and XIAP and by enforcing activation of the initiator caspase-10 as well as of the executioner caspases-6, -7, and -3.
- Published
- 2004
67. Prostate apoptosis response gene-4 (par-4) abrogates the survival function of p185(BCR-ABL) in hematopoietic cells
- Author
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Martin Ruthardt, Dieter Hoelzer, Paris S. Mitrou, Natasa Kukoc-Zivojnov, Elena Puccetti, Eckhart Weidmann, Kai U Chow, Marion Bergmann, and Simone Boehrer
- Subjects
Male ,Cancer Research ,animal structures ,Cell Survival ,Cell ,Fusion Proteins, bcr-abl ,Apoptosis ,Biology ,Transfection ,law.invention ,Colony-Forming Units Assay ,Mice ,Western blot ,law ,hemic and lymphatic diseases ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Cloning, Molecular ,Molecular Biology ,Interleukin 3 ,ABL ,medicine.diagnostic_test ,Intracellular Signaling Peptides and Proteins ,Prostate ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Hematopoietic Stem Cells ,Leukemia, Lymphocytic, Chronic, B-Cell ,Rats ,Haematopoiesis ,medicine.anatomical_structure ,Immunology ,Cancer research ,Suppressor ,Interleukin-3 ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Cell Division - Abstract
Objective Prostate apoptosis response gene-4 (par-4) is deregulated in acute and chronic lymphatic leukemia. Given its pro-apoptotic role in neoplastic lymphocytes and evidence that par-4 antagonizes oncogenic Ras in solid tumors, we hypothesized that par-4 may act as a tumor suppressor impairing transformation induced by p185 BCR-ABL . Materials and Methods The capacity of par-4 to interfere with factor independence induced by p185 BCR-ABL and V12ras was evaluated by analysis of factor-independent growth of p185 BCR-ABL / par-4 and V12ras/par-4 tranduced cells. The expression of par-4 and p185 BCR-ABL by the respective constructs was controlled by Western blot analysis. Activated Ras was detected by pull-down assay in the cell clones expressing p185 BCR-ABL in the absence and presence of par-4. Results Expression of p185 BCR-ABL causes factor independence, signifying a conversion toward a transformed phenotype in hematopoietic precursors. We demonstrate that par-4 completely abolishes factor independence induced by p185 BCR-ABL and partially abrogates factor independence caused by activated V12ras. Evaluating the underlying molecular mechanisms, we show that par-4 hinders activation of oncogenic Ras and causes concomitant disruptions of p185 BCR-ABL -mediated signaling. Conclusion We provide the first evidence that par-4 exhibits an antitransforming capacity by antagonizing p185 BCR-ABL -induced factor-independent proliferation in hematopoietic cells.
- Published
- 2003
68. Expression and function of prostate-apoptosis-response-gene-4 in lymphatic cells
- Author
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Eckhart Weidmann, Dieter Hoelzer, Kai U Chow, Martin Ruthardt, Simone Boehrer, and Paris S. Mitrou
- Subjects
Cancer Research ,T-Lymphocytes ,Down-Regulation ,Apoptosis ,Jurkat cells ,Models, Biological ,Pathogenesis ,Jurkat Cells ,medicine ,Humans ,RNA, Messenger ,Caspase ,Regulation of gene expression ,biology ,Intracellular Signaling Peptides and Proteins ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Cell biology ,Enzyme Activation ,Gene Expression Regulation, Neoplastic ,Leukemia ,Lymphatic system ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,biology.protein ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Ex vivo - Abstract
Inhibition of apoptosis contributes to the pathogenesis of lymphatic malignancies. In particular, the elevated expression of Bcl-2 is considered to be a marker of poor prognosis, since increased levels of Bcl-2 confer longevity as well as chemoresistance. After demonstrating an inverse expressional pattern of Bcl-2 and prostate-apoptosis-response-4 (Par-4) in ex vivo cells of patients suffering from acute lymphatic leukemia (ALL) as well as a deregulated expression of Par-4 in acute and chronic lymphatic neoplasias, the molecular mechanisms underlying these results were investigated. Thus, it was demonstrated that in neoplastic lymphatic cells Par-4 exerts a proapoptotic role augmenting chemosensitivity by down-regulating Bcl-2, promoting disruption of mitochondrial membrane potential and enforcing caspase-activation. Moreover, Par-4 enables cells to circumvent inhibition of the central executioner caspase-3 by alternative activation of caspases following a decrease in expression levels of inhibitors of apoptosis proteins (IAP).
- Published
- 2003
69. In lymphatic cells par-4 sensitizes to apoptosis by down-regulating bcl-2 and promoting disruption of mitochondrial membrane potential and caspase activation
- Author
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Simone, Boehrer, Kai U, Chow, Florian, Beske, Natasa, Kukoc-Zivojnov, Elena, Puccetti, Martin, Ruthardt, Christine, Baum, Vivek M, Rangnekar, Dieter, Hoelzer, Paris S, Mitrou, and Eckhart, Weidmann
- Subjects
Cytarabine ,Intracellular Signaling Peptides and Proteins ,Down-Regulation ,Antineoplastic Agents ,Apoptosis ,Intracellular Membranes ,Transfection ,Caspase Inhibitors ,Membrane Potentials ,Mitochondria ,Enzyme Activation ,Isoenzymes ,Jurkat Cells ,Proto-Oncogene Proteins c-bcl-2 ,Doxorubicin ,Caspases ,Humans ,Poly(ADP-ribose) Polymerases ,Apoptosis Regulatory Proteins ,Carrier Proteins - Abstract
Inhibition of apoptosis is a hallmark of malignancies of the hematopoetic system. Previous studies in nonhematopoetic cells demonstrated that the prostate-apoptosis-response-gene-4 (Par-4) is up-regulated in cells undergoing programmed cell death and that Par-4 exerts its proapoptotic effect by down-regulating Bcl-2. After showing the aberrant expressional pattern of Par-4 in neoplastic lymphocytes as well as demonstrating inverse expressional patterns of Par-4 and Bcl-2 in malignant cells of patients suffering from acute lymphocytic leukemia, we assessed the functional consequences of Par-4 overexpression during apoptosis in Jurkat T lymphocytes. We show that in lymphatic cells Par-4 overexpression decreases the level of Bcl-2, whereas Bax, the proapoptotic counterpart of Bcl-2, retains unaltered levels. Moreover, Par-4 overexpression is accompanied by cleavage of poly(ADP-ribose) polymerase (PARP). Despite these effects, overexpression of Par-4 alone is not sufficient to induce apoptosis but markedly increases the rate of apoptosis on treatment with different chemotherapeutic agents. On chemotherapeutic treatment Par-4 overexpression enhances disruption of mitochondrial membrane potential, PARP-cleaving activity, as well as activation of caspase-3. The hypothesis of caspase-dependency of Par-4-promoted apoptosis is additionally supported by demonstrating complete abrogation of programmed cell death after pretreatment with a broad spectrum caspase-inhibitor. On inhibition of caspase-3 overexpression of Par-4 enables lymphatic cells to alternatively activate caspases-9, -6, and -7 by diminishing the influence of the inhibitors of apoptosis proteins (IAPs) cIAP1 and XIAP. Our study is the first to identify Par-4 as a proapoptotic protein in lymphatic cells, outlining a model of action evaluating the role of Bcl-2/Bax, as well as demonstrating the impact of Par-4 expression on PARP cleavage, disruption of mitochondrial membrane potential, caspase activation, and interactions with inhibitors of apoptosis proteins.
- Published
- 2002
70. Dual TCR-expressing T lymphocytes in health and disease
- Author
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Dieter Kabelitz, Thomas Hinz, and Eckhart Weidmann
- Subjects
Leukemia, T-Cell ,Lymphocyte ,T cell ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,Autoimmunity ,HIV Infections ,Biology ,medicine.disease_cause ,Lymphoma, T-Cell ,Peripheral blood mononuclear cell ,Mice ,Antigen ,medicine ,Immunology and Allergy ,Animals ,Humans ,Allorecognition ,T-cell receptor ,General Medicine ,medicine.disease ,Inflammatory Bowel Diseases ,Leukemia ,medicine.anatomical_structure ,Immunologic Memory - Abstract
The authors briefly review recent experimental advances in elucidating the role of dual T cell receptor (TCR)-expressing lymphocytes in the developement of diseases with special emphasis on autoimmunity. Moreover, they summarize present knowledge about these cells concerning their proportion among peripheral blood mononuclear cells, their functionality, and their impact on allorecognition and memory both in humans and in mice. Finally, they describe disease-associated clonal expansions of dual TCR-expressing cells in humans, most of which have been observed in peripheral T cell malignancies. Other cases occurred in inflammatory bowel disease and in HIV infection. They propose that expression of two distinct TCR on malignant T lymphocytes might be much higher than is suggested by the few cases described so far, and that their presence might impinge on therapeutic immunization strategies which make use of the TCR itself as a target.
- Published
- 2001
71. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure
- Author
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Richard T. D'Aquila, Andrew N. Phillips, Stuart Bloor, Peter Gute, Veronica Miller, Schlomo Staszewski, Brendan Larder, Caroline A. Sabin, Javier Martinez-Picado, Thomas Lutz, Eckhart Weidmann, Holger F. Rabenau, and Kurt Hertogs
- Subjects
Adult ,Male ,Anti-HIV Agents ,Immunology ,Population ,HIV Infections ,Drug resistance ,Virus Replication ,Virus ,Drug Administration Schedule ,Immunology and Allergy ,Medicine ,Humans ,Treatment Failure ,education ,Sida ,Salvage Therapy ,education.field_of_study ,biology ,business.industry ,Drug Resistance, Microbial ,Middle Aged ,Viral Load ,biology.organism_classification ,Regimen ,Infectious Diseases ,Mutation ,HIV-1 ,Reverse Transcriptase Inhibitors ,Ritonavir ,Drug Therapy, Combination ,Female ,Viral disease ,business ,Viral load ,medicine.drug - Abstract
Objective: To analyse the immunological and virological effects of treatment interruptions in HIV-1-infected patients with treatment failure and multidrug-resistant virus. Methods: Drug susceptibility was assessed using Antivirogram and genotypic analysis was based on population and clonal sequencing for 48 patients who had interrupted treatment (greater than or equal to 2 months). Results: Treatment interruption resulted in viral load increases (mean 0.7 log(10) copies/ml; P = 0.0001) and CD4 cell count decreases (mean 89 x 10(6) cells/l; P = 0.0001). A complete shift to wild-type virus at the phenotypic, genotypic and clonal level was observed in 28/45 patients. These patients differed from those that did not show a shift to wild type in baseline CD4 cell counts (192 versus 59 x 10(6) cells/I; P = 0.007) and in the relationship between baseline viral load and CD4 cell count (no correlation versus a significant negative correlation; P = 0.008). Response to re-initiation of treatment fell with increasing viral load [relative hazard (RH) 0.33; P = 0.001] and with increasing total number of drugs with reduced susceptibility (RH 0.51; P = 0.0003); it improved with the number of new drugs received (RH 2.12; P = 0.0002) and a shift to wild type (RH 5.22, P = 0.006). Conclusions: Changes in surrogate markers suggest that treatment provided benefit in spite of virological failure and resistant virus. Although patients with a shift to wildtype virus responded better in the short term to treatment re-initiation, the long-term effects are not known and the risk of immune deterioration needs to be carefully considered. (C) 2000 Lippincott WiIliams & Wilkins.
- Published
- 2001
72. Dendritic Cells from AML Patients in Complete Remission are Capable to Present Antigen to Autologous T Lymphocytes
- Author
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Daniela K. Schui, Dieter Hoelzer, Björn Schneider, L. Singh, A. Krapohl, and Eckhart Weidmann
- Subjects
Lymphocyte Transfusion ,business.industry ,Toxoid ,Dendritic cell ,medicine.disease ,Leukemia ,Haematopoiesis ,Antigen ,hemic and lymphatic diseases ,Immunology ,Medicine ,Cytotoxic T cell ,business ,Cytotoxicity - Abstract
Evidence for immunogenicity of AML blasts is supported by graft versus leukemia reaction, the effect of donor lymphocyte transfusion and in vitrostudies with cytotoxic T cells. Because of the potency of dendritic cells (DC) to present antigens, it seems feasible to study, whether functional DC can be generated in AML patients with the perspective of future vaccination strategies. Therefore, peripheral blood was obtained from 19 patients in complete remission of AML and 13 healthy controls (HC). DC were established from monocytes by culturing in the presence of GM-CSF and IL-4 for 8 days. To collect mature DC GM-CSF and TNF-α were added to cultures until day 12. At days 8 and 12 cell numbers were counted and expression of surface markers typical for DC was analyzed by flowcytometry. The ability of established DC to present antigens was tested using tetanus toxoid (TT) as a recall antigen. Furthermore day 8 DC were incubated with lysates of leukemic blasts and cocultured with autologous lymphocytes. Cytotoxicity against autologous blast cells was measured by a PKH67 assay. The numbers of DC were significantly lower in AML patients >2 months after chemotherapy as compared to HC (p=0,04) or AML patients during hematopoietic regeneration following chemotherapy (p=0,01). There was no statistical difference in expression of surface markers by DC from AML patients and HC. CD83, the most specific marker for DC, was comparable in both groups (day 8: HC 11-62%, AML 10-67% p=0,07; day 12: HC 42-91%, AML 23-78% p=0,08). TT was presented efficiently to autologous lymphocytes by DC from HC and AML patients. At an effector:target-ratio of 20:1 lymphocytes from one patient stimulated with DC pulsed with blast lysates killed 20,3% of autologous blasts compared to 13,6% lysis by effector cells from HC. Cloning of these T cells is currently in progress. In conclusion dendritic cells can be efficiently generated in AML patients especially during hematopoietic regeneration following chemotherapy. Preliminary results indicate the activation of autologous T cells after stimulation by DC pulsed with blast lysates.
- Published
- 2001
73. The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia
- Author
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Eckhart Weidmann, Lothar Bergmann, Dieter Hoelzer, Ulrich Maurer, H Ackermann, T. Karakas, and Cornelius Miething
- Subjects
Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Apoptosis ,Biology ,urologic and male genital diseases ,Gene expression ,medicine ,Humans ,RNA, Messenger ,WT1 Proteins ,Gene ,Aged ,Aged, 80 and over ,urogenital system ,fungi ,Myeloid leukemia ,Adult Acute Myeloid Leukemia ,Wilms' tumor ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,female genital diseases and pregnancy complications ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,Leukemia, Myeloid ,Acute Disease ,Cancer research ,Bone marrow ,Follow-Up Studies - Abstract
The Wilms tumor gene wt1 and the protooncogene bcl-2 are upregulated in acute myeloid leukemia (AML) and are known to regulate or to inhibit the onset of apoptosis. Since wt1 has been shown to regulate the expression of bcl-2, we investigated the association of the expression of these genes and their prognostic relevance in AML. Leukemic blasts from the bone marrow of 152 patients with newly diagnosed AML were analyzed for bcl-2 and wt1 mRNA expression using RT-PCR and quantitative PCR. Therapy outcome was correlated with the level of bcl-2 and wt1 transcripts. Bcl-2-specific mRNA was detectable in 127/152 (84%) patients and wt1 mRNA in 113/152 (74%) patients with AML. In monocytic subtypes the frequency of bcl-2 and wt1 transcripts was significantly lower. The expression of bcl-2 mRNA was correlated significantly with that of wt1 mRNA (P0.0001). In AML patients60 years, high expression of bcl-2 and wt1 was associated with a reduced rate of continuing complete remission (CCR, P = 0.002 and P = 0.005, respectively) and increased death rate (P = 0.0002 and P = 0.04, respectively) in contrast to patients60 years, where the expression of bcl-2 or wt1 had no prognostic impact. Based on the coexpression of bcl-2 and wt1, we established a prognostic model defining three risk groups with significant differences in CCR rate (P = 0.01), overall survival (P0.04) and disease-free survival (P0.03). Thus, bcl-2 and wt1 mRNA expression are associated with response and long-term outcome in AMLs. The coexpression of these genes allows determination of prognostic groups with high predictive value for overall and disease-free survival.
- Published
- 2000
74. Induction of apoptosis by 2-chloro-2'deoxyadenosine (2-CdA) alone and in combination with other cytotoxic drugs: synergistic effects on normal and neoplastic lymphocytes by addition of doxorubicin and mitoxantrone
- Author
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Eckhart Weidmann, Hans Martin, Mathias J. Rummel, Petra Jantschke, Dieter Hoelzer, Paris S. Mitrou, Farsad Pourebrahim, Juergen Stein, Simone Boehrer, Simone Napieralski, Juergen Ries, and Kai U Chow
- Subjects
Cancer Research ,2-Chloroadenosine ,Lymphoma ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,In vivo ,medicine ,Tumor Cells, Cultured ,Cytotoxic T cell ,Humans ,Doxorubicin ,Active metabolite ,Etoposide ,Mitoxantrone ,Deoxyadenosines ,Dose-Response Relationship, Drug ,Chemistry ,Drug Synergism ,Hematology ,Dose–response relationship ,Oncology ,medicine.drug - Abstract
2-CdA is active as a single agent in the treatment of low-grade lymphomas. We analyzed the induction of apoptosis by 2-CdA alone (n=5) and in combination with other drugs in peripheral lymphocytes from 25 patients with leukemic low-grade lymphomas and from 25 healthy volunteers. 2-CdA was tested in 4 escalating concentrations (0.05 microg/ml to 0.4 microg/ml). Linear regressions showed a dose dependent apoptosis rate of 0.29 x microg 2-CdA/ml + 0.11 (r2=0.88, p=0.006) in normal cells and 0.41 x microg 2-CdA/ml + 0.15 (r2=0.88, p=0.005) in leukemic cells. Intracellular metabolization of 2-CdA into 2-CdA-5'mono-, -di- and the active metabolite -triphosphate was analyzed by HPLC and paralleled the dose dependent increase of apoptosis. The combination of 2-CdA with doxorubicin or mitoxantrone had a synergistic effect on the induction of apoptosis (p
- Published
- 2000
75. Quantification of human interleukin 18 mRNA expression by competitive reverse transcriptase polymerase chain reaction
- Author
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Eckhart Weidmann, Karin Ballas, Uwe Kalina, Dieter Hoelzer, Thomas S. Dobmeyer, Oliver G. Ottmann, Martine Pape, and Stefan Klein
- Subjects
Cell type ,medicine.medical_treatment ,Immunology ,Biology ,Biochemistry ,Peripheral blood mononuclear cell ,Binding, Competitive ,Sensitivity and Specificity ,medicine ,Immunology and Allergy ,Humans ,RNA, Messenger ,Molecular Biology ,Phytohaemagglutinin ,Reverse Transcriptase Polymerase Chain Reaction ,Monocyte ,Interleukin-18 ,Reproducibility of Results ,Hematology ,Templates, Genetic ,Molecular biology ,Reverse transcriptase ,Cytokine ,medicine.anatomical_structure ,biology.protein ,Leukocytes, Mononuclear ,Linear Models ,Interleukin 18 ,CD8 - Abstract
Interleukin 18 (IL-18) is a recently identified cytokine, originally called interferon γ inducing factor, due to its capacity to induce interferon γ production in Th1 type cells. IL-18 is expressed by a wide variety of cell types including mononuclear phagocytes, osteoblasts, keratinocytes and adrenal cortex cells. To quantify human IL-18 mRNA expression in small-scale cell samples the authors developed a competitive reverse transcriptase polymerase chain reaction using a competitive template as an internal standard. This assay was demonstrated as a valid, sensitive and precise tool to quantify human IL-18 mRNA expression. IL-18 mRNA expression of primary peripheral blood monocytes, CD4 + T cells, CD8 + T cells, B cells and NK cells was assessed by competitive RT-PCR. Basal IL-18 expression could be detected in all types of peripheral blood mononuclear cells (PBMC). The kinetics of IL-18 mRNA expression in PBMC from healthy donors was defined in vitro after monocyte-specific (lipopolysaccharide LPS), T-cell-specific (anti-CD3) and polyclonal-unspecific stimulation (phytohaemagglutinin PHA). Only LPS led to a strong increase of IL-18 mRNA expression peaking after 2 h. These results indicate that IL-18 is expressed constitutionally by all major PBMC subtypes. However, only monocyte specific stimulation resulted in a significant induction of IL-18 mRNA expression suggesting activated monocytes e.g. in inflammation as the main source of IL-18 expression.
- Published
- 1999
76. Wilms tumor gene (wt1) mRNA is equally expressed in blast cells from acute myeloid leukemia and normal CD34+ progenitors
- Author
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Eckhart Weidmann, Lothar Bergmann, Dieter Hoelzer, T. Karakas, and Ulrich Maurer
- Subjects
Immunology ,CD34 ,Gene Expression ,Antigens, CD34 ,Biology ,Biochemistry ,Precursor cell ,medicine ,Humans ,RNA, Messenger ,Progenitor cell ,WT1 Proteins ,Myeloid leukemia ,Wilms' tumor ,Cell Biology ,Hematology ,medicine.disease ,Hematopoietic Stem Cells ,DNA-Binding Proteins ,Haematopoiesis ,medicine.anatomical_structure ,Leukemia, Myeloid ,Cord blood ,Acute Disease ,Cancer research ,Bone marrow ,Transcription Factors - Abstract
To the Editor : In a recent issue of Blood , Inoue et al[1][1] reported aberrant overexpression of Wilms tumor gene (wt1) mRNA in leukemic blasts compared with immature hematopoietic progenitors. CD34+ bone marrow and cord blood cells derived from nine healthy volunteers were sorted into 10 subsets
- Published
- 1997
77. Establishment and characterization of a new, factor-independent acute myeloid leukemia line designated Ei501
- Author
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T. Karakas, Eckhart Weidmann, J. Brieger, Paris S. Mitrou, Lothar Bergmann, Dieter Hoelzer, Ulrich Maurer, and U Pascheberg
- Subjects
Cancer Research ,Cytotoxicity test ,Tumor suppressor gene ,Adolescent ,Biology ,Polymerase Chain Reaction ,Proto-Oncogene Mas ,Translocation, Genetic ,Cell Line ,Immunophenotyping ,Antigens, CD ,Bone Marrow ,HLA Antigens ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Humans ,In Situ Hybridization, Fluorescence ,DNA Primers ,Chromosomes, Human, Pair 15 ,Myeloid leukemia ,Chromosome Mapping ,Hematology ,HLA-DR Antigens ,Leukemia, Myeloid, Acute ,Oncology ,Karyotyping ,Immunology ,Cancer research ,Cytokines ,Female ,Line (text file) ,Chromosomes, Human, Pair 7 ,Chromosomes, Human, Pair 17 ,Chromosomes, Human, Pair 8 - Abstract
We established a factor-independent acute myeloid leukemia cell line, designated Ei501. The line has been growing in RPMI 1640 media for 18 months and can be maintained without addition of growth factors. Ei501 is positive for myeloperoxidase and negative for esterase and PAS. Cytogenetic analysis revealed the FAB M3 associated t(15;17) translocation and a translocation of the chromosomes 7 and 8: 46 XX, -7, +t(7;8)(q32;q13), t(15;17)(q22;q12). This karyotype was confirmed by fluorescence in situ hybridization. Ei501 cells express AML-associated surface markers such as CD13, CD33 and CD38. Although 42% of the patient's blast cells were CD34-positive, the line lacks surface expression of CD34. Furthermore the line has a number of characteristics which are detectable in blasts from AML patients, such as surface adhesion molecules, cytokines such as TGF-beta, cytokine receptors such as the IL-2 receptor beta and gamma chains or the IL-4 receptor and the genes for the transcription factor wt-1 (Wilms' tumor gene) and for the proto-oncogene bcl-2, both shown to be present in the majority of patients with AML. Additionally the line can be used as target in cytotoxicity assays using IL-2 activated cytotoxic lymphocytes as effector cells. In conclusion, besides a rare karyotype the Ei501 cell line has several features common in AML, and may therefore be used as a model to study pathogenetic mechanisms in acute myeloid leukemia.
- Published
- 1997
78. Detection of the Wilms Tumor Gene (wt-1) mRNA in Complete Remission of AML Frequently Precedes Relapse
- Author
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J. Brieger, Paris S. Mitrou, Eckhart Weidmann, Lothar Bergmann, Dieter Hoelzer, and Ulrich Maurer
- Subjects
Acute leukemia ,business.industry ,Wilms' tumor ,medicine.disease ,Peripheral blood mononuclear cell ,Minimal residual disease ,Pathogenesis ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Precursor cell ,Gene expression ,Cancer research ,Medicine ,Bone marrow ,business - Abstract
Leukemic blast cells taken from 83 patients with AML at time of diagnosis and 20 patients during follow-up in complete remission were examined for the expression of wt-1 mRNA. For this purpose blast cells were isolated from bone marrow or peripheral blood and total RNA was extracted. The wt-1 transcription was subsequently studied via RT-PCR. Mononuclear cells and bone marrow from healthy persons were used as controls. Wilms’ tumor mRNA was detectable in 67 out of 83 cases of AML (81%). None of the 13 healthy controls expressed wt-1. After achieving cytological Complete Remission (CR) 14/20 patients studied lost wt-1 expression. In 7/8 patients in CR persistence or reappearance of wt-1 expression preceded relapse of the disease. Response to therapy and survival did not correlate with wt-1 mRNA expression in newly diagnosed AML before therapy. Our data show that expression of wt-1 mRNA is widely spread in AML and may be a useful marker for detection of minimal residual disease (MRD) in acute leukemia. The follow-up data strongly suggest that analysis of wt-1 gene expression via PCR in CR may be a sensitive technique for the early detection of relapse. Analysis of wt-1 expression accompanying routine bone marrow aspiration may be useful to define the quality of remission and early prediction of relapse of the disease. Its relevance to outcome, follow-up, and detection of MRD, however, as well as its potential role in the pathogenesis of acute leukemia, remain to be confirmed by ongoing studies.
- Published
- 1997
79. IL-2 Receptor (IL-2R) Alpha, Beta, and Gamma Chains Expressed on Blasts of Acute Myelocytic Leukemia May Not Be Functional
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Lothar Bergmann, Dieter Hoelzer, Eckhart Weidmann, K. Fenchel, J. Brieger, and Paris S. Mitrou
- Subjects
Acute leukemia ,medicine.anatomical_structure ,Real-time polymerase chain reaction ,Cell culture ,Chemistry ,hemic and lymphatic diseases ,medicine ,Cytotoxic T cell ,Bone marrow ,IL-2 receptor ,Molecular biology ,Alpha chain ,K562 cells - Abstract
Preliminary clinical studies including IL-2 in chemotherapeutic strategies for treatment of acute myelocytic leukemia suggest that IL-2 may improve the overall outcome of the patients [1, 2]. To date, the mechanisms of eradication of blast cells are still unclear. Cytotoxic T and NK cells or secondary cytokines released after administration of IL-2 have been discussed to contribute to the elimination of leukemic cells [3–5]. However, it is important to know, whether IL-2 may directly influence AML blasts [6]. In initial sudies, using flow cytometry, we found expression of considerable levels of the IL-2R alpha chain on blast cells in a low proportion of patients with AML. However, the IL-2R beta chain was more frequently expressed ranging from 0% to 98%. To confirm these results on a transcriptional level, we studied the expression of RNA of the IL-2R α, β, and γ chains by RT PCR in the bone marrow of 39 newly diagnosed patients with AML and in three AML derived cell lines. RNA for all three IL-2R chains was expressed in lines KG1, HEL 92.1.7 and K562. Surface expression of the IL-2R β chain was observed in all three lines, but of the α chain only in KG1 cells. In comparison with unstimulated cell lines incubation of the three lines with various amounts of IL-2 over 3 and 14 days did not influence their growth, measured by cell numbers and 3H-thymidin incorporation. RNA for the α chain was detectable in 12/39 patients, of the β chain in 10/39 patients and the γ chain in 29/39 patients with AML. Altogether the data suggest that the IL-2R expressed on AML blast cells may be incomplete and not functional. In future studies, functional properties of IL-2 R on blast cells obtained from newly diagnosed patients with AML will have to be investigated.
- Published
- 1996
80. Expression of CD7 and CD15 on Leukemic Blasts Are Prognostic Parameters in Patients with Acute Myelocytic Leukemia — Irrelevance of CD34
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Eckhart Weidmann, Christine Heller, Arnold Ganser, K. Fenchel, Lothar Bergmann, Dieter Hoelzer, J. Brieger, Paris S. Mitrou, and Bernhard Wörmann
- Subjects
Acute leukemia ,biology ,medicine.drug_class ,business.industry ,CD34 ,CD15 ,Monoclonal antibody ,Antigen ,hemic and lymphatic diseases ,medicine ,biology.protein ,Cancer research ,Clinical significance ,Antibody ,business ,Direct fluorescent antibody - Abstract
In order to investigate the clinical significance of surface markers in correlation to therapeutic outcome of induction therapy in acute myelocytic leukemia (AML), the blasts from 94 adult patients with AML were analyzed prospectively. We used a panel of 32 monoclonal antibodies reactive with normal lymphoid and myeloid cells at various stages of differentiation in a direct immunofluorescence technique. There was no strict correlation of antigen expression with the French-American-British (FAB) classification. All patients were treated with an intensive induction treatment. Staining by two antibodies had a prognostic value. The achievement of complete remission (CR) was significantly correlated with a high (> 50% of cells) expression of CD7 in de novo AML. All patients (8/39) with de novo AML and high expression of CD7 achieved CR, so far (p < 0.03). The high expression of CD15 was also correlated with the achievement of CR (p < 0.05). In contrast to recent reports, we found no correlation between CD34 surface expression and the prognosis of the disease. These results confirm earlier reports of antigenic heterogeneity in AML, and indicate that immunologically defined subgroups of AML patients which are of potential clinical significance can be identified.
- Published
- 1996
81. The Inhibition of Lymphokine Activated Killer Cell Activation Mediated by AML Culture Supernatants Might Be Due to Transforming Growth Factor Beta1
- Author
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Daniela K. Schui, Lothar Bergmann, Dieter Hoelzer, Paris S. Mitrou, Eckhart Weidmann, and J. Brieger
- Subjects
Lymphokine-activated killer cell ,biology ,Chemistry ,Lymphokine ,Transforming growth factor beta ,medicine.disease ,Immunosurveillance ,Leukemia ,Immune system ,hemic and lymphatic diseases ,Immunology ,medicine ,biology.protein ,Cytotoxic T cell ,Transforming growth factor - Abstract
The cytotoxic activity of peripheral mononuclear cells (PMNC) from patients with acute myelogenous leukemia (AML) is usually reduced at time of diagnosis [1, 2]. Production and release of immunosuppressive cytokines by leukemic blast cells might be a cause for impaired cytotoxic activity and immunosurveillance of leukemic cells. Indeed, soluble but yet undefined factors secreted by AML blasts have been described to be reponsible for inhibited cytotoxic activity in AML patients [3, 4]. Transforming growth factor beta (TGF-β) has been reported to be a strong inhibitor of cytotoxic activity of lymphokine activated killer (LAK) cells [5–9]. In ovarian carcinoma, increased TGF-β secretion was shown to suppress various immune functions [10]. It may be suggested that TGF-β may be an important factor in AML, too, causing immunosuppression.
- Published
- 1996
82. The Amplification of the Wilms Tumor Gene (wt-1) mRNA Using the Polymerase Chain Reaction Technique (PCR) May Enable Sensitive Detection of Small Blast Populations in AML
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K. Fenchel, Paris S. Mitrou, J. Brieger, Lothar Bergmann, Dieter Hoelzer, and Eckhart Weidmann
- Subjects
Chemotherapy ,Messenger RNA ,medicine.medical_treatment ,Wilms' tumor ,Biology ,medicine.disease ,Molecular biology ,Peripheral blood mononuclear cell ,law.invention ,medicine.anatomical_structure ,law ,Precursor cell ,medicine ,Bone marrow ,Gene ,Polymerase chain reaction - Abstract
Leukemic cells from 52 patients with AML were examined for the expression of wt-1 mRNA. Blast cells were isolated from bone marrow or peripheral blood. Total RNA was extracted and wt-1 transcription was studied via RT-PCR. Mononuclear cells and bone marrow from healthy persons were used as controls. Cell surface antigens were determined using FACS-analysis. In dilution experiments the detection limit was assessed as 1 out of 10000 cells. Wilms’ tumor mRNA was detectable in 41 out of 52 cases of AML (79%). None of the 13 controls expressed wt-1. After chemotherapy, six out of eleven patients in complete remission (CR) lost wt-1 expression completely. The remaining five patients expressed wt-1 mRNA at the same or a lower level. The significance of wt-1 persistance for desease free survival will have to be defined.
- Published
- 1996
83. Subanalysis of the StiL NHL 1–2003 Study: Achievement of Complete Response with Bendamustine-Rituximab (B-R) and CHOP-R in the First-Line Treatment of Indolent and Mantle Cell Lymphomas Results in Superior Survival Compared to Partial Response
- Author
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Norbert Niederle, Heinz A. Duerk, Martina Stauch, Christina Balser, Axel Hinke, Chrisoph Losem, G.-Andre Banat, Mathias J. Rummel, Manfred Welslau, Ulrich von Grünhagen, Harald Ballo, Wolfram Brugger, Eckhart Weidmann, Juergen Barth, Dorothea Kofahl-Krause, Fritz Roller, Gerhard Heil, Alexander Burchardt, Georg Maschmeyer, and Ulrich Kaiser
- Subjects
Bendamustine ,medicine.medical_specialty ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,CHOP ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Tolerability ,Partial response ,Internal medicine ,medicine ,Mantle cell lymphoma ,Rituximab ,business ,Complete response ,medicine.drug - Abstract
Abstract 2724 Background: The NHL 1 study, a prospective, multicenter, randomized, phase 3 study which compared B-R and CHOP-R as first-line treatment in indolent lymphomas and mantle cell lymphoma (MCL), demonstrated a significant benefit in progression-free survival (PFS) as well as improved tolerability for B-R compared with CHOP-R. Here we present an analysis of the impact of response quality on outcome. Methods: 514 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. Results: The overall response rate in the 514 pts (261 B-R; 253 CHOP-R) was 92.7% and 91.3% in the B-R and CHOP-R arms, respectively (as presented at the last ASCO meeting, J Clin Oncol 30, 2012 (suppl; abstr 3). A complete response (CR) was observed in 39.8% in the B-R arm and in 30% in the CHOP-R arm (p=0.021). The achievement of CR was associated with a significantly prolonged PFS and overall survival (OS) (Table 1). Analysis by treatment arm revealed a trend for superior PFS and a significantly improved OS for patients achieving CR following treatment with B-R. In the CHOP-R arm, patients in CR had a significantly superior PFS compared to those in PR with a trend to superior OS. Regardless of the quality of response, PFS was superior with B-R versus CHOP-R: For patients in CR, the median PFS was not reached with B-R, whereas for CHOP-R it was 53.7 months (p=0.0204). In patients achieving PR, treatment with B-R resulted in a median PFS of 57.2 months, and this was 30.9 months with CHOP-R (p=0.0002). We noted a statistically significant difference in CR rates between male (n=272, median age 63 years) and female (n=242, median age 64 years) patients. The CR rate was 28.6% in male patients and 42.1% in female patients (p=0.0016). Female patients had a longer median PFS (51.4 months) compared to male patients (38.6 months), however, this difference was not statistically significant (p=0.0866). Conclusions: Patients in CR following first-line treatment in our study had a significantly longer PFS and OS compared to those achieving a PR. Therefore, our results strongly suggest an association between quality of response and outcome. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2012
84. The Wilms' tumor gene is frequently expressed in acute myeloblastic leukemias and may provide a marker for residual blast cells detectable by PCR
- Author
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Lothar Bergmann, Eckhart Weidmann, Dieter Hoelzer, J. Brieger, Paris S. Mitrou, and Ulrich Maurer
- Subjects
Adult ,Genetic Markers ,Pathology ,medicine.medical_specialty ,Myeloid ,Genes, Wilms Tumor ,Tumor suppressor gene ,Molecular Sequence Data ,CD34 ,Gene Expression ,Peripheral blood mononuclear cell ,Polymerase Chain Reaction ,Medicine ,Humans ,RNA, Messenger ,Aged ,Base Sequence ,business.industry ,Wilms' tumor ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Minimal residual disease ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Bone marrow ,business - Abstract
Summary Background The tumor suppressor gene wt-1 was isolated by cytogenetic deletion analysis of patients with Wilms' tumor (wt-1). This gene encodes for a zinc finger DNA-bind-ing protein with transcription-repressing properties. During normal ontogenesis it is expressed in a time- and tissue-dependent manner mainly in the kidneys and gonads. Recently, the expression of wt-1 in acute leukemias (AL) was reported. Here we investigated the prognostic potential of wt-1 mRNA expression during the course of the disease using the PCR technique. Patients and methods Blast cells from 83 patients with newly diagnosed AML and 20 AML patients during follow-up in complete remission were analyzed for wt-1 mRNA expression. Peripheral blood mononuclear cells (PBMNC) and bone marrow (BM) from healthy persons (n = 13) and sorted CD34-positive cells from normal donors (n = 4) were used as negative controls Results Wt-1-specific m-RNA was detectable in 67/83 (81%) patients with AML. Normal donors did not express wt-1 m-RNA but in 1/4 sorted CD34+ cell samples a weak amplified product was observed. After achieving cytologica] CR 14/20 studied patients lost wt-1 expression. In 7/8 patients in morphological CR the reappearance of wt-1 expression preceded relapse of the disease, in 1/8 patients wt-1 remained positive in CR. Response to therapy, disease-free survival, overall survival and FAB-subtype did not correlate with wt-1 m-RNA expression in newly diagnosed AML before therapy Conclusions In the majority of acute leukemias wt-1 is expressed and probably blast cell-associated, at least in levels detectable by PCR. Wt-1 mRNA was detectable in bone marrow cells of AML patients in clinical CR The results strongly suggest that the persistence or reappearance of wt-1 predicts relapse of the disease prior to morphological relapse
- Published
- 1995
85. AML blasts variably express interleukin 2 receptor alpha, beta or gamma chains without measurable effects on proliferation, cytokine message expression or surface expression of adhesion molecules upon stimulation with interleukin 2
- Author
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Lothar Bergmann, Eckhart Weidmann, Paris S. Mitrou, Dieter Hoelzer, and J. Brieger
- Subjects
Interleukin 2 ,Cancer Research ,Receptor expression ,medicine.medical_treatment ,Molecular Sequence Data ,Biology ,Cell surface receptor ,Bone Marrow ,Gene expression ,medicine ,Tumor Cells, Cultured ,Humans ,RNA, Neoplasm ,Receptor ,DNA Primers ,Base Sequence ,Cell adhesion molecule ,Receptors, Interleukin-2 ,Hematology ,Molecular biology ,Leukemia, Myeloid, Acute ,Real-time polymerase chain reaction ,Cytokine ,Oncology ,Leukocytes, Mononuclear ,Cytokines ,Interleukin-2 ,Cell Adhesion Molecules ,Cell Division ,medicine.drug - Abstract
Preliminary clinical studies including interleukin 2 (IL-2) in chemotherapy strategies for treatment of acute myeloblastic leukemia (AML) suggest that IL-2 may improve the disease-free survival of the patients. Because of reports showing interleukin 2 receptor expression on AML blasts, it is important to know whether IL-2 may directly influence these leukemic cells. In initial studies using flow cytometry to analyze surface expression of interleukin 2 receptors (IL-2R), we found expression of the IL-2R α chain on blast cells in 26% and of the IL-2R β-chain in 81% of the patients. To confirm these results at the transcriptional level, we studied the expression of RNA of the IL-2R α, β, and γ chains by RT-PCR in the bone marrow of 38 newly diagnosed patients with AML and in three AML-derived cell lines. RNA of the α chain was detectable in 11 38 patients, the β chain in 10 38 patients and the γ chain in 30 38 patients with AML. Blast cells obtained from colonies growing in semisolid media expressed mRNA for IL-2R. RNA for all three IL-2R chains was expressed in lines KG1, HEL 92.1.7 and K562. In comparison with unstimulated cell lines, incubation of the three lines with various amounts of IL-2 over 3 and 14 days did not increase their growth or change message expression of IL-2R, IL-10, and TGF-β and surface expression of the adhesion molecules CD 11, CD 18, CD 29 and CD 54. In conclusion, despite expression of IL-2 receptors, AML blasts do not respond to IL-2 by proliferation, message expression for various cytokine genes and surface expression of cellular adhesion molecules.
- Published
- 1995
86. Bone marrow-derived T-cell clones obtained from untreated acute myelocytic leukemia exhibit blast directed autologous cytotoxicity
- Author
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J. Brieger, Eckhart Weidmann, Ulrich Schwulera, Dieter Hoelzer, K. Fenchel, B. Jahn, Paris S. Mitrou, and Lothar Bergmann
- Subjects
Cytotoxicity, Immunologic ,Cancer Research ,Myeloid ,T cell ,CD3 ,Receptors, Antigen, T-Cell, alpha-beta ,T-Lymphocytes ,Bone Marrow Cells ,medicine ,Cytotoxic T cell ,Humans ,Interferon gamma ,Cells, Cultured ,biology ,Hematology ,medicine.disease ,Virology ,Molecular biology ,Clone Cells ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,biology.protein ,Cytokines ,Bone marrow ,CD8 ,medicine.drug - Abstract
The eradication of minimal residual blast populations by activation of autologous cytotoxic cells with interleukin 2 (IL-2) is a new promising tool in the treatment of acute myelocytic leukemia (AML). However, the immunological effector cells are not yet clearly defined. The present study was designed to investigate the presence of cytotoxic precursor cells in active AML and to identify phenotypical and functional characteristics of autologous anti-leukemic cytotoxic effector cells. For this purpose, mononuclear cells (MNC) containing at least 70% leukemic blasts were isolated from bone marrow of untreated AML and cultured in the presence of 3000 IU/ml recombinant IL-2 (rIL-2) for 6-8 weeks. Under these conditions, T-cells were selected in the bone marrow cultures and overgrew the leukemic blasts. The resulting T-cell populations were cloned by limiting dilution and the clones obtained were characterized for their phenotypical and functional patterns. Totally, cloning resulted in 68 clones and a few cell lines. The clonality was verified by RT PCR analysis of TCR V beta gene expression. All clones obtained stained positive for CD2, CD3, DR and CD56. The vast majority (68%) of T-cell clones/lines was CD4+, a few clones expressed CD8 (19%) or CD4 and CD8, and four clones were of TCR gamma delta origin. Seven of 15 clones tested, including three CD4+, two CD8+ and two TCR gamma delta(+)-clones were found to be cytotoxic against autologous leukemic blast cells. All except one clone expressed oncolytic activities against allogeneic blasts too. One of the TCR gamma delta(+)-clones demonstrated NK activity by lysis of K562 targets. The majority of the T-cell-clones released IL-2, IL-8, TNF-alpha, GM-CSF but only a few IFN gamma and expressed high levels of mRNA for IL-2, TGF-beta and IL-10. None of the clones was found to produce IL-3, IL-4, IL-7 and TNF-beta. The data provide evidence of the existence of T-cell precursors in untreated AML bone marrow differentiating to cytotoxic cells with activity against autologous and allogeneic AML blast cells.
- Published
- 1995
87. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study
- Author
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Dorothea Kofahl-Krause, Gerhard Heil, Manfred Welslau, Ulrich von Gruenhagen, Heinz A. Duerk, Harald Ballo, Ulrich Kaiser, A. Banat, Martina Stauch, Eckhart Weidmann, Christina Balser, Christoph Losem, Mathias J. Rummel, Axel Hinke, Wolfram Brugger, Juergen Barth, Georg Maschmeyer, and Norbert Niederle
- Subjects
Bendamustine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Patient characteristics ,CHOP ,Surgery ,Indolent lymphoma ,First line treatment ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Clinical endpoint ,Rituximab ,In patient ,business ,medicine.drug - Abstract
3 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in indolent lymphoma and MCL and was presented at ASH 2009 including a comprehensive safety analysis. Here we present an updated analysis with a cut-off date for 31 Oct 2011. Methods: 549 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a max of 6 cycles. The primary endpoint was PFS. Results: 514 pts randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. At a median follow-up of 45 months, PFS was significantly prolonged with B-R compared with CHOP-R (HR 0.58, 95% CI 0.44–0.74; P 60 years (n=315). In pts with...
- Published
- 2012
88. HLA restriction and T-cell-receptor V beta gene expression of cytotoxic T lymphocytes reactive with human squamous-cell carcinoma of the head and neck
- Author
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Eckhart Weidmann, Jonas T. Johnson, Theresa L. Whiteside, Satoshi Yasumura, Ronald B. Herberman, and Hideki Hirabayashi
- Subjects
Cancer Research ,biology ,CD3 ,Receptors, Antigen, T-Cell, alpha-beta ,T-cell receptor ,Histocompatibility Antigens Class I ,Histocompatibility Antigens Class II ,Antibodies, Monoclonal ,T lymphocyte ,Major histocompatibility complex ,Flow Cytometry ,Virology ,Molecular biology ,Tongue Neoplasms ,CTL ,Oncology ,Antigen ,biology.protein ,Carcinoma, Squamous Cell ,Tumor Cells, Cultured ,Cytotoxic T cell ,Cytokines ,Humans ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
A human cytotoxic-T-lymphocyte (CTL) line capable of killing autologous tumor (AuTu) cell targets was established from peripheral-blood lymphocytes of a patient with squamous-cell carcinoma of the tongue. The cultured CTL were CD3+CD8+CD11b-HLA-DR+T cell receptor (TCR) alpha/beta+. When tested in 4-hr 51Cr-release assays against various lines of squamous-cell carcinoma of the head and neck (SCCHN) and a variety of non-squamous human tumor and normal cell targets, the CTL were found to lyse the autologous SCCHN cell line (PCI-50) and 7 allogeneic SCCHN lines: PCI-1, -2, -4A, -4B, -13, -30 and -38. Of these tumor cell lines, PCI-13, -30 and -38 shared HLA-A2 locus with the AuTu, PCI-50, while PCI-4A and -4B shared HLA-B44 with AuTu. Lysis of AuTu (A2+B44+), PCI-13 (A2+B44-) and PCI-4B (A2- B44+) by the CTL was efficiently inhibited by monoclonal antibodies (MAbs) to CD3, CD8, TCR alpha/beta or the major-histocompatibility-complex (MHC)-class-I antigens. MAbs to HLA-A2 antigens inhibited lysis of PCI-50 or PCI-13 targets by the CTL. In cold-target inhibition assays, unlabeled PCI-4B or PCI-13 cells inhibited CTL lysis of AuTu targets. The CTL incubated in the presence of the HLA-A2+ SCCHN PCI-50 or -13, but not an HLA-A2+ gastric carcinoma, produced TNF-alpha, IFN-gamma and GM-CSF. The CTL were tested for their TCR V beta gene expression by polymerase chain reaction (PCR). At week 10 in culture, the time of the highest AuTu cytotoxicity mediated by the CTL line, V beta 6 was expressed by 26% of T cells. Three clones, obtained by limiting dilution from 10-week CTL and selected for high cytotoxicity against AuTu, were found to be V beta6+. Further analysis of the specificity of these clones indicated lytic activity against PCI-13 (A2+B44-), but not PCI-4B (A2-B44+) targets. In 16-week cultures, which retained AuTu cytotoxicity as well as V beta 6 expression, TCR V beta 2 was also expressed at high frequency (29%), and AuTu-reactive clones were found to be V beta 2+. Our results indicate that at least 2 different CTL populations (V beta 6+ and V beta 2+) are able to recognize SCCHN-associated antigen(s) and that the V beta 6+ T cells are HLA-A2 restricted, while V beta 2+ T cells may be HLA-B44 restricted.
- Published
- 1994
89. The T-Cell Receptor β Chain Variable Region Repertoire in Fresh and Cultured Lymphocytes Isolated from Human Malignant Melanomas
- Author
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Eckhart Weidmann, Massimo Trucco, Elaine M. Elder, Theresa L. Whiteside, and Ronald B. Herberman
- Subjects
Repertoire ,T-cell receptor ,Immunology ,Biology ,Molecular biology - Published
- 1994
90. Daily alternating administration of high-dose alpha-2b-interferon and interleukin-2 bolus infusion in metastatic renal cell cancer. A phase II study
- Author
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Hans-Martin Enzinger, Klaus Fenchel, Eckhart Weidmann, Dieter Jonas, Paris S. Mitrou, Lothar Bergmann, and Bernhard Jahn
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Lymphocytosis ,medicine.medical_treatment ,Alpha interferon ,Phases of clinical research ,Interferon alpha-2 ,Gastroenterology ,Drug Administration Schedule ,Interferon-gamma ,Leukocyte Count ,T-Lymphocyte Subsets ,Internal medicine ,medicine ,Humans ,Infusions, Intravenous ,Carcinoma, Renal Cell ,Interferon alfa ,Aged ,Aged, 80 and over ,business.industry ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Remission Induction ,Interferon-alpha ,Receptors, Interleukin-2 ,Immunotherapy ,Middle Aged ,medicine.disease ,Rash ,Kidney Neoplasms ,Lymphocyte Subsets ,Recombinant Proteins ,Surgery ,Drug Combinations ,Oncology ,Toxicity ,Interleukin-2 ,Female ,medicine.symptom ,Neoplasm Recurrence, Local ,business ,Progressive disease ,medicine.drug - Abstract
Background Both interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) have some efficacy in renal cell cancer (RCC) as single agents. Additionally, there is some evidence for additive or synergistic antitumoral activity of IL-2 and alpha-IFN in vitro and possibly in vivo. Based on these data, the authors initiated a Phase II trial with a combination of recombinant IL-2 (rIL-2) and recombinant alpha-IFN (alpha-rIFN) in advanced RCC. Methods Thirty-six assessable patients with metastatic RCC were entered in this Phase II trial using a daily alternating schedule of alpha-rIFN and rIL-2. Over a period of 14 days, the patients received daily alternating treatment with 10 x 10(6) IU/m2 of recombinant alpha-2b-interferon subcutaneously and 18 x 10(6) IU/m2 of rIL-2 as a 1-hour intravenous infusion. This treatment schedule was repeated every sixth week up to a maximum of four cycles. After the second cycle, patients were examined for response. Patients with stable disease or better received two additional cycles of therapy. Patients with progressive disease were available for other strategies. Results Thirty-six patients entered the trial and were assessable for toxic effects. Thirty of 36 patients completed at least two cycles and were assessable for response. Nine patients achieved an objective response: 2 had complete responses (CR) and 7 had partial responses (PR). Three patients had a minor response. No effect was observed in patients with local relapse or bone metastases. A relapse-free survival length of 6 months or longer was seen in both patients with CR (12, 23 + months) and in four of seven patients with PR (6, 7, 12, 12 months). The toxicity was moderate and included fever and nausea in most patients, and hypotension, fatigue, skin rash, and arthralgia in a minority of the patients. No Grade 4 and only occasionally Grade 3 toxicity was observed. Fluid retention was negligible. The monitoring of immunologic parameters showed a significant rebound lymphocytosis including cytotoxic (CD56+) cells; in responders the peak of lymphocytosis occurred up to 1 week later than in nonresponders. Peripheral lymphocytes obtained after therapy showed only a slight increase of natural killer cell and lymphokine-activated killer cell activity. During therapy, there was a great release of secondary cytokines as tumor necrosis factor-alpha, gamma-interferon, and interleukin-6, with a peak level 2-4 hours after rIL-2 infusion. Conclusions In conclusion, daily alternating administration of alpha-rIFN and rIL-2 is effective in RCC with less toxicity, and the response rate is comparable to those of other immunotherapeutic schedules, including adoptive immunotherapeutic schedules, including adoptive immunotherapy and combinations of high-dose IL-2 and alpha-IFN.
- Published
- 1993
91. Interleukin-2 in the Treatment of Cancer Disease: Introduction of a Therapeutic Model and some Immunological Data
- Author
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Eckhart Weidmann, Bergmann L, P. Hechler, H. Grieser, P. S. Mitrou, and U. Schwulera
- Subjects
Interleukin 2 ,Effector ,business.industry ,Cancer ,Disease ,medicine.disease ,Therapeutic approach ,Immunology ,medicine ,Cytotoxic T cell ,In patient ,business ,Lymphocyte subsets ,medicine.drug - Abstract
Therapeutic administration of interleukin-2 (IL-2) in patients with metastatic cancer disease has been shown to lead to tumor regression [1]. This therapeutic approach is associated with the activation of cytotoxic cell populations [2], proliferation of various lymphocyte subsets [3], and induction of secondary cytokines released by different effectors of the human immunes system [4].
- Published
- 1993
92. Bendamustine Plus Rituximab Versus Fludarabine Plus Rituximab In Patients with Relapsed Follicular, Indolent and Mantle Cell Lymphomas – Final Results of the Randomized Phase III Study NHL 2–2003 on Behalf of the StiL (Study Group Indolent Lymphomas, Germany)
- Author
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Harald Ballo, Eckhart Weidmann, Ulrich Kaiser, Christoph Losem, Mathias J. Rummel, Axel Hinke, Manfred Welslau, Ulrich von Gruenhagen, Christina Balser, Lothar Mueller, Martina Stauch, Michael Sandherr, Wolfram Brugger, Juergen Barth, Norbert Niederle, and Julia Vereschagina
- Subjects
Bendamustine ,medicine.medical_specialty ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,Biology ,medicine.disease ,Biochemistry ,Gastroenterology ,Fludarabine ,International Prognostic Index ,Maintenance therapy ,Leukocytopenia ,Internal medicine ,medicine ,Mantle cell lymphoma ,Rituximab ,medicine.drug - Abstract
Abstract 856 Introduction: Promising results have been observed in two phase II studies evaluating the combination of bendamustine plus rituximab (B-R) in patients (pts) with relapsed/refractory follicular, other indolent or mantle cell lymphomas (MCL) (Rummel et al. JCO 2005; Robinson et al. JCO 2008). Fludarabine plus rituximab (F-R) is an established treatment option in this setting. Therefore, we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of B-R versus F-R for pts with relapsed follicular (FL), indolent or MCL. Patients and methods: 219 pts with relapsed FL, indolent or MCL in need of treatment were randomized to rituximab 375 mg/m2 (day 1) plus either bendamustine 90 mg/m2 (days 1+2) or fludarabine 25 mg/m2 (days 1–3) q 28 days for a maximum of 6 cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended; however in cases of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 q 3 months for up to 2 years) in both arms, following regulatory approvals in this setting. Results: 11 pts were not evaluable due to protocol violations, and were not followed further. A total of 208 pts were evaluable for the final analysis (109 B-R; 99 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, International Prognostic Index (IPI), follicular IPI (FLIPI), bone marrow infiltration and extranodal involvement. Most pts had stage IV (71.6% B-R; 60.6% F-R) or stage III disease (21.1% B-R and 25.3% F-R, respectively). Median patient age was 68 yrs (range 38–87). Patients had received a median of 1 prior therapy (range 1–7). Histological subtypes were distributed equally between the B-R and F-R arms: follicular 45.9 % and 47.5%, respectively; immunocytoma 11.9% and 11.1%; MCL 20.2% and 21.2%; other indolent lymphomas 23% and 20.2%. A median number of 6 cycles were given in both treatment arms, with 75.2% of B-R pts and 53.4% of F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2010), the median observation time was 33 months. Median PFS was significantly prolonged with B-R compared with F-R (30 vs 11 months; hazard ratio [HR] 0.51, 95 % confidence interval [CI] 0.34–0.67; p There were no significant differences in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy or infectious episodes between groups. Hematologic toxicities were also similar between arms: 8.9% grade 3/4 neutropenia with B-R vs 9.1% with F-R; 11.8% grade 3/4 leukocytopenia with B-R vs 12.4% with F-R. The overall incidence of serious adverse events was similar for the B-R and F-R groups (17.4 and 22.2%, respectively). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.21, 95% CI 0.22–0.67; p=0.0008) and PFS (HR 0.27, 95% CI 0.27–0.59; p< 0.0001) in the small group of 40 pts who received this treatment (23 B-R, 17 F-R), compared with those who did not. Although the numbers are too small in this non-randomized comparison to draw some validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: These data confirm the efficacy of B-R in pts with relapsed FL, indolent or MCL, and, in this setting, demonstrate a superior PFS benefit for this regimen in comparison with F-R. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
93. No Elevated Rates of Treatment-Related Myelodysplastic Syndromes and Second Solid Tumors Following Therapy with Bendamustine Compared with Other Anti-Lymphoma Regimes for Low-Grade Non-Hodgkin's Lymphoma
- Author
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Axel Hinke, Arnold Ganser, Wolfram Brugger, Jürgen Barth, Georg Maschmeyer, A Tenzer, Chrisoph Losem, Ulrich von Grünhagen, Axel Matzdorff, Norbert Niederle, Mathias J. Rummel, Manfred Welslau, Harald-E. Balló, Christina Balser, Gerhard Heil, and Eckhart Weidmann
- Subjects
Bendamustine ,medicine.medical_specialty ,Chemotherapy ,business.industry ,Myelodysplastic syndromes ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Lymphoma ,Non-Hodgkin's lymphoma ,Fludarabine ,Surgery ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Rituximab ,Mantle cell lymphoma ,business ,medicine.drug - Abstract
Abstract 3090 Introduction: Long term survival among patients (pts) with low grade/indolent Non-Hodgkin lymphoma (iNHL) is increasingly common, and as a consequence, a consideration of potential therapy-related sequelae, such as secondary neoplasia (sNPL), is of particular importance. Bendamustine plus rituximab (B-R) is an effective treatment option with a favorable toxicity profile in pts with iNHL. However, no data have been reported concerning later, therapy-associated complications with B-R. The aim of this study was to determine the incidence of therapy-related myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and solid tumors after B-R, in comparison with other anti-lymphoma chemotherapy regimens, in pts with follicular (FL), other indolent or mantle cell lymphoma (MCL). Patients and methods: Data for this analysis were obtained from 2 randomized studies, including a total of 697 pts: 1) StiL-study NHL-1, comparing B-R (bendamustine 90 mg/m2, d1+2, rituximab 375 mg/m2, d1; q 28 days) with CHOP-R (q 21 days) as first-line therapy in 513 pts (260 B-R, 253 CHOP-R) (median age 64 yrs, range 31–83); 2) StiL-study NHL-2, comparing B-R with F-R (fludarabine 25mg/m2, d1–3, rituximab 375mg/m2, d1; q 28 days) in 184 pts (median age 68 yrs, range 38–87) with relapsed disease (96 B-R, 88 F-R). Patients in this NHL-2 study had received a median of 1 prior therapy (range 1–7). Result: At the time of this analysis (May 2010), the median observation time was 35 months for NHL-1 pts and 33 months for NHL-2 pts. Most pts in both studies received 6 cycles of therapy. In the NHL-1 study, 16 pts (6.2%) developed sNPL after B-R as first-line treatment, compared with 19 (7.5%) after CHOP-R. Most (87.5%) sNPL were solid tumours: 4 gastrointestinal, 4 urothelium, 2 prostate, 2 squamous epithelium, 1 bronchial, and 1 adrenal after B-R; 6 gastrointestinal, 5 prostate, 3 bronchial, 2 breast, 1 melanoma, 1 urothelium, and 1 endocrinal pancreas after CHOP-R. The rate of secondary hematological NPL did not differ between arms; 1 MDS and 1 T-cell-lymphoma after B-R, 1 AML and 1 Hodgkin lymphoma after CHOP-R. The median time from initiation of study therapy to diagnosis of sNPL was 18.5 months for B-R, and 14 months for CHOP-R. 5 pts in the B-R group, and 2 in the CHOP-R group received additional chemotherapy after completing study therapy, and before diagnosis of sNPL. In the NHL-2 study, 6 pts (6.3%) developed sNPL after B-R as relapse therapy, compared with 9 (10.3%) after F-R (p=0.42). Of these, 3 pts in the B-R group, and 2 pts in the F-R group developed a secondary hematological NPL (2 MDS, 1 Hodgkin lymphoma after B-R; 2 AML/MDS after F-R). Solid tumors were observed in 3 pts following B-R (2 urothelium, 1 squamous epithelium), and in 8 pts following F-R (3 squamous epithelium, 2 bronchial, 1 gastrointestinal, 1 urothelium, 1 anal). The median time from initiation of study therapy to diagnosis of sNPL was 33 months for the B-R group and 24.5 months for the F-R group. Conclusion: This ongoing evaluation shows comparable rates of secondary MDS/AML and other sNPL between B-R and CHOP-R or F-R. This observation, combined with data from other studies showing improved efficacy with B-R compared with CHOP-R or F-R, confirm the value of B-R as a treatment option in patients with follicular, indolent or MCL. Longer follow-up of the patient cohorts reported here will provide important additional information on the rate of sNPL with B-R compared with other anti-lymphoma regimens. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
94. Rapid cytokine release in cancer patients treated with interleukin-2
- Author
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Lothar Bergmann, Eckhart Weidmann, Paris S. Mitrou, Roland Kirsten, and Josef Stock
- Subjects
Interleukin 2 ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Endogeny ,Interferon-gamma ,Internal medicine ,Neoplasms ,medicine ,Carcinoma ,Immunology and Allergy ,Humans ,Infusions, Intravenous ,Carcinoma, Renal Cell ,Melanoma ,Pharmacology ,business.industry ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Radioimmunoassay ,Immunotherapy ,medicine.disease ,Kidney Neoplasms ,Kinetics ,Endocrinology ,Cytokine ,Cytokines ,Interleukin-2 ,Tumor necrosis factor alpha ,business ,Perfusion ,medicine.drug - Abstract
Serum concentrations of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-6 (IL-6), interleukin-1 (IL-1) and interferon-alpha (IFN-alpha) were determined by commercially available enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) in cancer patients treated with recombinant IL-2 (rIL-2) either as 1-h infusion (3 or 5 x 10(6)/m2) or continuous intravenous infusion for 5 days (3 x 10(6)/m2/day). A significant increase of TNF-alpha and IL-6 serum levels was observed in each patient. One-hour infusion of IL-2 induced a very rapid secretion of TNF-alpha, IL-6 and IFN-gamma with considerably higher peak levels than during IL-2 continuous intravenous infusion. IFN-gamma was released into the blood of all patients receiving IL-2 1-h infusion, but only occasionally during or after IL-2 continuous intravenous infusion. Neither IFN-alpha nor IL-1 were detectable in the serum before, during, or following IL-2 treatment in all patients studied. The kinetics of IL-2 after 1-h infusion fitted to a two-compartment model, suggesting the synthesis of considerable amounts of endogenous IL-2. Following IL-2 1-h infusion, rising TNF-alpha serum levels preceded the increase of serum IFN-gamma or IL-6. The serum peak levels of IFN-gamma and IL-6 decreased rapidly with a half-life of 0.29 to 2.5 h. The concentration time profiles of TNF following 1-h infusion of IL-2 demonstrated a considerably longer half-life than that of intravenously administered recombinant TNF as done in other studies.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
95. Treatment of severe systemic lupus erythematosus with immunoadsorption and intravenous immunoglobulins
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Helmut Geiger, U. F. Mondorf, Eckhart Weidmann, R. Wigand, and A. Viertel
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medicine.medical_specialty ,Immunosorbent technique ,Blisibimod ,business.industry ,Intravenous Immunoglobulins ,Anesthesiology ,Pain medicine ,Medicine ,Critical Care and Intensive Care Medicine ,business ,Immunoadsorption ,Dermatology ,Anti-SSA/Ro autoantibodies - Published
- 2000
96. Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany)
- Author
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Gerhard Heil, Dieter Hoelzer, Christina Balser, Ulrich Kaiser, Georg Maschmeyer, Harald Ballo, Dorothea Kofahl-Krause, Eckhart Weidmann, Mathias J. Rummel, Manfred Welslau, Christoph Losem, Heinz A. Duerk, Wolfram Brugger, Norbert Niederle, Juergen Barth, Axel Hinke, Fritz Roller, Ulrich von Gruenhagen, and A. Banat
- Subjects
Bendamustine ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,CHOP ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Leukocytopenia ,Tolerability ,Internal medicine ,medicine ,Mantle cell lymphoma ,Rituximab ,Progression-free survival ,business ,medicine.drug - Abstract
Abstract 405 Introduction: Promising results have been observed in two phase-II studies evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas (Rummel et al., JCO 2005; Robinson et al., JCO 2008). In order to further investigate the role of the combination B-R we initiated a multicenter randomized phase-III study in October 2003 to compare efficacy and safety of B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for patients with follicular (FL), indolent and mantle cell lymphomas (MCL). Patients and Methods: 549 patients (pts) in need of treatment for their disease were randomized to receive Rituximab 375 mg/m2 (day 1) plus either Bendamustine 90 mg/m2 (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Patients characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration and extranodal involvement did not statistically significant differ between both arms. The median patient age was 64 years (range 31-83) (64 yrs for B-R and 63 yrs for CHOP-R). Most patients were in stage IV (76,9% in BR and 77,5 in CHOP-R) and stage III (19,2% in B-R and 18,6% in CHOP-R). Histologies were distributed equally between B-R and CHOP-R: follicular 55% and 56%, mantle cell 18% and 19%, and other indolent lymphomas 27% and 24%, respectively. Prophylactic use of antibiotics or growth factors were not generally recommended in this protocol. Results: Of the 549 pts 36 pts were not evaluable: 10 did not receive any study medication, 9 due to withdrawal of consent, 13 due to incorrect diagnosis (4 × DLBCL, 3 × CLL, 2 × MM, 1 × HD, 3 × solid tumors), and 4 for other reasons. 513 randomized pts are evaluable for the final analysis (B-R: n=260; CHOP-R: n=253). Out of these 9 pts were not evaluable for response evaluation: 4 pts (3 × CHOP-R, 1 × B-R) due to early death in neutropenic sepsis, 3 pts due to a subsequent change of therapy after severe toxicity in 1st cycle of CHOP-R, 1 B-R pt due to progress of disease, and 1 B-R due to early death. All patients were counted for evaluation of PFS, overall survival (OS), event-free survival (EFS; an event was defined by a response less than a partial response, disease progression, relapse, or death from any cause), and for time to next treatment (TTNT). A median number of 6 cycles was given in both treatment arms each. 82% of B-R pts and 86% of CHOP-R pts received 6 cycles. At the time of analysis in August 2009, the median observation time was 32 months. Overall response rate for pts treated with B-R was similar to the CHOP-R group (93,8% vs 93,5%, respectively). The CR rate was significantly higher with 40,1% for B-R compared to 30,8% for CHOP-R (p=0.0323). The median PFS, EFS and TTNT were significantly longer after B-R compared to after CHOP-R: PFS 54,8 months for B-R versus (vs) 34,8 months for CHOP-R (p=0.0002), Hazard Ratio (HR) 0.5765 (95% confidence interval (CI) 0.4292 to 0.7683); EFS 54 months for B-R vs 31 months for CHOP-R (p=0.0002, HR 0.6014 (95% CI 0.4515 to 0.7845); and TTNT median not yet reached in the B-R group vs 40,7 months in the CHOP-R group (p=0.0002; HR 0.5416, 95% CI 0.3897 to 0.7491). OS did not differ between both groups at this point of time. Thus far, 67 deaths have been observed (B-R: 34; CHOP-R: 33). CHOP-R treatment was more frequently associated with serious adverse events (SAE) (n=49 in B-R vs n=74 in CHOP-R). Significant differences in hematologic toxicities were observed for neutropenia grade 3+4 (BR 10,7% vs CHOP-R 46,5%; p Conclusions: In this final analysis the combination of Bendamustine plus Rituximab improves PFS and CR rates while showing a better tolerability profile. These promising results suggest that B-R does have the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Disclosures: Rummel: Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Maschmeyer:OrthoBiotech: .
- Published
- 2009
97. Interleukin-2 and interferon-alpha2b as a daily alternating schedule in advanced renal cell cancer
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Paris S. Mitrou, Eckhart Weidmann, K. Fenchel, Dietger Jonas, H. M. Enzinger, and Lothar Bergmann
- Subjects
Interleukin 2 ,Nephrology ,medicine.medical_specialty ,business.industry ,Urology ,medicine.medical_treatment ,Alpha interferon ,Phases of clinical research ,Immunotherapy ,medicine.disease ,Gastroenterology ,Metastasis ,Internal medicine ,medicine ,business ,Interferon alfa ,Progressive disease ,medicine.drug - Abstract
Interferon-alpha (IFN-α) and interleukin-2 (Il-2) are effective as single agents in metastatic renal cell cancer (RCC) with response rates of 15–30%. Additionally, IFN-α is assumed to act synergistically with Il-2 in the induction of lymphokine-activated killer cells. (LAK cells) in vitro. With the aims of increasing the response rate by combining both cytokines and of reducing side effects, we started a clinical trial with a daily alternating schedule of 10×106 units/m2 s.c. rIFN-α2b (Essex, Munich, FRG) and 3×106 Cetus units/m2 rIL-2 (EuroCetus, Frankfurt, FRG) in the form of 1 h infusions over a period of 14 days. Patients found to have progressive disease after two cycles of therapy were withdrawn from the study; patients with stable disease or better received two further cycles. Of the 27 patients included in the study, 22 (16 male, 6 female) are evaluable for response. In 1 patient with multiple pulmonary metastases complete remission was achieved, in 5 patients partial remission, and in 2 a minor response. The schedule was practicable; the main side effects were influenza-like symptoms, fatigue and hypotension. Some patients suffered from arthralgias and erythemas up to 3 weeks after finishing the therapy cycle. On the whole, the side effects seem to be less severe than those arising from schedules using continuous Il-2 infusions.
- Published
- 1991
98. Bendamustine Plus Rituximab Versus CHOP Plus Rituximab in the First-Line-Treatment of Patients with Follicular, Indolent and Mantle Cell Lymphomas: Results of a Randomized Phase III Study of the Study Group Indolent Lymphomas (StiL)
- Author
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Ulrich Kaiser, Dorothea Kofahl-Krause, Harald Ballo, Eckhart Weidmann, Martina Stauch, Mathias J. Rummel, Norbert Niederle, Christina Balser, Gerhard Heil, Wolfram Brugger, Wolfgang Knauf, Heinz A. Duerk, Manfred Welslau, and Ulrich von Gruenhagen
- Subjects
Bendamustine ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,CHOP ,medicine.disease ,Interim analysis ,Biochemistry ,Gastroenterology ,Regimen ,Leukocytopenia ,Tolerability ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Mantle cell lymphoma ,Rituximab ,business ,medicine.drug - Abstract
Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented. Objective: In October 2003, we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). The trial was calculated to power the study to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause. The study is closed according to the planned recruitment schedule. Results: 546 patients have been randomized. For this second interim analysis, 437 patients are evaluable for response (B-R: n=221; CHOP-R: n=212). Median patient age is 64 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 41% for B-R compared to 33% for CHOP-R. The median follow-up time for both groups is 28 months. Thus far, 50 deaths have been observed (B-R: 25; CHOP-R: 25). Progressive or relapsed disease has been documented during the follow-up period: 58 in pts treated with B-R and 75 in the CHOP-R group. The median EFS for B-R is not yet reached, the median EFS for CHOP-R is 39 months with no statistical significant difference for the EFS between both groups. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (0% with B-R vs. 89% CHOP-R) and a lower number of infectious complications (number of patients with infections of any grade were 56 (25%) in the B-R group vs. 78 (37%) in CHOP-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 36% CHOP-R treated pts compared with 19% in pts treated with B-R, while in the CHOP-R group more frequently G-CSF was used. Conclusions: In this second interim analysis, the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. Further updated results will be presented at this time.
- Published
- 2008
99. Bendamustine Plus Rituximab Versus CHOP Plus Rituximab in the First-Line Treatment of Patients with Indolent and Mantle Cell Lymphomas - First Interim Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany)
- Author
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Christina Balser, U. von Gruenhagen, Wolfram Brugger, K. Schalk, Heinz A. Duerk, Manfred Welslau, Harald Ballo, Eckhart Weidmann, F. Rothmann, Gerhard Heil, Christoph Losem, Mathias J. Rummel, Ulrich Kaiser, Dorothea Kofahl-Krause, Norbert Niederle, A. Banat, Martina Stauch, W. U. Knauf, Axel Matzdorff, and Dieter Hoelzer
- Subjects
Bendamustine ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,CHOP ,medicine.disease ,Interim analysis ,Biochemistry ,Gastroenterology ,Surgery ,Regimen ,Tolerability ,Leukocytopenia ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Mantle cell lymphoma ,Rituximab ,business ,medicine.drug - Abstract
Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented. Objective: In October 2003 we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). A sample size of 474 pts were calculated to power the study sufficiently to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause. Results: So far 439 patients have been randomized. 273 patients are evaluable for response for this first interim analysis (B-R: n=139; CHOP-R: n=134). Median patient age is 63 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 51% for B-R compared to 40% for CHOP-R. The median observation time for both groups is 17 months. Thus far, 15 deaths have been observed (B-R: 7; CHOP-R: 8). Progressive or relapsed disease has been documented during the follow-up period: 27 in pts treated with B-R and 32 in the CHOP-R group. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (40% CHOP-R vs. 0% with B-R) and a lower number of infectious complications (41 in CHOP-R pts vs. 19 in the B-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 41% CHOP-R treated pts compared with 12% in pts treated with B-R. Conclusions: In this first interim analysis the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. The study will be closed in December 2007 according to the planned patient recruitement schedule. Updated results will be presented at this time.
- Published
- 2007
100. High Dose Cytarabine Salvage Regimen Combined with Bortezomib Is Feasible and Highly Effective in Relapsed Mantle Cell Lymphoma
- Author
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Martin Dreyling, Eckhart Weidmann, Michael Unterhalt, Wolfgang Hiddemann, Christoph von Schilling, Kathleen Jentsch-Ullrich, Rudolf Mueck, Martin Bentz, Robert Rohrberg, and Oliver Weigert
- Subjects
medicine.medical_specialty ,Bortezomib ,business.industry ,Immunology ,Salvage therapy ,Cell Biology ,Hematology ,CHOP ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Regimen ,Internal medicine ,medicine ,Cytarabine ,Mantle cell lymphoma ,business ,Progressive disease ,Febrile neutropenia ,medicine.drug - Abstract
Introduction: Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with an especially poor prognosis. However, molecular targeted therapy may alter the natural history of disease. Bortezomib (BZ) is a potent, selective and reversible inhibitor of the 26S proteasome thereby interfering with intracellular protein homeostasis. Various clinical phase II trials revealed significant efficacy of BZ monotherapy in relapsed MCL with approximately 40% response rate, but rare CR and short duration of response. Based on our preclinical data demonstrating synergy of BZ and cytarabine (Ara-C) we performed a pilot study to explore the clinical impact of such combined approach. Treatment: 2 g/m2 Ara-C was applied on day 2 and 3 (1 g/m2 in patients with impaired hematopoiesis or age >60 years) combined with BZ 1.5 mg/m2 iv bolus (day 1 and 4). In addition, dexamethasone 40 mg was given over a 4 day period. R was added to the outlined regimen in 6 patients (375 mg/m2). Treatment was repeated in 3 week intervals for a total of 4 cycles with staging procedures performed after 2 and 4 cycles. Results: After informed consent 8 patients with relapsed or refractory advanced stage MCL were treated accordingly to the outlined protocol. Median age was 65 years (54–76), 5 patients were male. Median number of prior systemic therapies was 4 (2–7). All patients had previously been treated with CHOP and at least one rituximab (R)-containing regimen, 2 patients previously failed BZ monotherapy, and none of them was considered eligible for myeloablative treatment. Currently data from 7 patients are available for analysis of toxicity and response. At time of analysis, a total of 22 cycles has been applied with a median follow-up of 214 days (119–366). As expected, hematologic toxicity CTC grade III/IV occurred in all 7 patients, but only one case of neutropenic fever (grade 3) and no major bleeding were observed. Ara-C dose was reduced in 5 patients. Two patients developed new onset or worsening of preexisting polyneuropathy. Dose of BZ had to be reduced in 1 patient and stopped after cycle 2 in another patient with preexisting polyneuropathy. Of note, 2 patients developed herpes zoster (grade 2). In 3 patients treatment was stopped after cycle 2 due to insufficient response (progressive disease, stable disease and minimal response, respectively). In the 4 patients completing 4 cycles 1 CR and 3 PR were archieved. Conclusion: Salvage therapy with high-dose Ara-C combined with BZ in relapsed or refractory MCL was associated with considerable but manageable hematotoxicity and only few infectious complications. The high efficacy in heavily pretreated patients justifies a comparative trial of the European MCL Network evaluating a high-dose cytarabine containing regimen +/− BZ.
- Published
- 2006
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