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Anthony F Greco - One of the best experts on this subject based on the ideXlab platform.
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maximizing therapeutic benefit of Rituximab maintenance therapy versus re treatment at progression in patients with indolent non hodgkin s lymphoma a randomized phase ii trial of the minnie pearl cancer research network
2005Co-Authors: John D Hainsworth, Sharlene Litchy, Don W Shaffer, Van L Lackey, Manuel Grimaldi, Anthony F GrecoAbstract:Purpose To compare the benefit of maintenance Rituximab therapy versus Rituximab re-treatment at progression in patients with previously treated indolent non-Hodgkin's lymphoma. Patients and Methods Between June 1998 and August 2002, 114 patients who had received previous chemotherapy for indolent non-Hodgkin's lymphoma were treated with a standard 4-week course of Rituximab. Patients with objective response or stable disease were randomly assigned to receive either maintenance Rituximab therapy (standard 4-week courses administered at 6-month intervals) or Rituximab re-treatment at the time of lymphoma progression. The duration of Rituximab benefit was measured from the date of first Rituximab treatment until the date other treatment was required. Results Ninety (79%) of 114 patients had objective response or stable disease after initial Rituximab treatment, and were randomly assigned to treatment. Progression-free survival was prolonged in the maintenance group (31.3 v 7.4 months; P = .007). Final overa...
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Rituximab as first line and maintenance therapy for patients with indolent non hodgkin s lymphoma
2002Co-Authors: John D Hainsworth, Sharlene Litchy, Howard A Burris, Daniel C Scullin, Steven W Corso, Denise A Yardley, Lisa H Morrissey, Anthony F GrecoAbstract:PURPOSE: To evaluate response to single-agent Rituximab in patients with indolent non-Hodgkin’s lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance Rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line Rituximab therapy. PATIENTS AND METHODS: Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received Rituximab 375 mg/m2 intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance Rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four Rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months. RESULTS: Sixty patients (97%) completed the first 4-week course of Rituximab and were assessable for...
Guillaume Cartron - One of the best experts on this subject based on the ideXlab platform.
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Rituximab and the risk of transformation of follicular lymphoma a retrospective pooled analysis
2018Co-Authors: Massimo Federico, Guillaume Cartron, Maria Dolores Caballero Barrigon, Luigi Marcheselli, Vittoria Tarantino, Martina Manni, Clementine Sarkozy, Sara Alonsoalvarez, Marielle J Wondergem, Armando LopezguillermoAbstract:Summary Background Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of Rituximab on the risk of histological transformation and its outcome. Methods 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation. Findings Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1–221; 2·5–97·5th percentile 5–160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9–8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5–6·2) in patients who received Rituximab and 8·7% (7·2–10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58–0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0–7·0) for patients who received induction Rituximab only and 3·6% (95% CI 2·3–5·5) for those treated with induction and maintenance Rituximab (HR 0·55, 95% CI 0·37–0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26–38). Survival after transformation did not differ between patients not exposed to Rituximab and those who received Rituximab in induction only (HR 0·94, 95% CI 0·69–1·28; p=0·70), and those who received Rituximab in induction and maintenance (0·96, 0·58–1·61; p=0·88). Interpretation The risk of histological transformation as a first event can be significantly reduced by the use of Rituximab. These findings support the need to inform patients using Rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab. Funding Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation.
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clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the prima study is not affected by fcgr3a and fcgr2a polymorphisms
2012Co-Authors: Herve Ghesquieres, Mariehelene Delfaularue, John F. Seymour, Guillaume Cartron, Fritz Offner, Pierre Soubeyran, Aurore Perrot, Pauline Brice, Reda Bouabdallah, Anne SonetAbstract:In patients with follicular lymphoma treated with single-agent Rituximab, single nucleotide polymorphisms in the FCGR3A gene are known to influence response and progression-free survival. The prognostic role of FCGR3A and FCGR2A polymorphisms in patients with follicular lymphoma treated with Rituximab and chemotherapy combination remains controversial and has not been evaluated in the context of Rituximab maintenance. FCGR3A and FCGR2A single nucleotide polymorphisms were evaluated in, respectively, 460 and 455 patients treated in the PRIMA study to investigate whether these were associated with response rate and patient outcome after Rituximab chemotherapy induction and 2-year Rituximab maintenance. In this representative patient cohort, complete and unconfirmed complete responses after Rituximab chemotherapy were observed in 65%, 67%, 66% (P = .86) and 60%, 72%, 66% (P = .21) of FCGR3A VV, VF, FF and FCGR2A HH, HR, RR carriers, respectively. After 2 years of Rituximab maintenance (or observation), response rates did not differ among the different genotypes. Progression-free survival measured from either treatment initiation or randomization to observation or maintenance was not influenced by these polymorphisms. These data indicate that FCGR3A and FCGR2A polymorphisms do not influence response rate and outcome when Rituximab is combined with chemotherapy or used as maintenance treatment. The PRIMA study is registered at www.clinicaltrials.gov as NCT00140582.
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Tumor burden influences exposure and response to Rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20
2009Co-Authors: David Dayde, David Ternant, Marc Ohresser, Stephanie Lerondel, Sabrina Pesnel, Herve Watier, Alain Le Pape, Pierre Bardos, Gilles Paintaud, Guillaume CartronAbstract:Clinical studies have shown a large interindividual variability in Rituximab exposure and its significant influence on clinical response in patients receiving similar doses of antibody. The aim of this study was to evaluate the influence of tumor burden on dose-concentration-response relationships of Rituximab. Murine lymphoma cells (EL4, 8 x 10(3)), transduced with human CD20 cDNA and transfected with luciferase plasmid (EL4-huCD20-Luc), were intravenously injected into C57BL/6J mice. Tumor burden detection, dissemination, and progression were evaluated quantitatively by in vivo bioluminescence imaging. Different doses of Rituximab (6, 12, 20, or 40 mg/kg) were infused 13 days after lymphoma cell inoculation, and Rituximab serum concentrations were measured by enzyme-linked immunosorbent assay. Without Rituximab, all mice developed disseminated lymphoma and died within 30 days, whereas a significant dose-response relationship was observed in mice receiving Rituximab. The 20-mg/kg dose was adequate to study interindividual variability in response because 23% of mice were cured, 59% had partial response, and 18% had disease progression. Rituximab concentrations were inversely correlated with tumor burden; mice with low tumor burden had high Rituximab concentrations. Furthermore, Rituximab exposure influenced response and survival. Finally, using a pharmacokinetic-pharmacodynamic model, we demonstrated that tumor burden significantly influenced Rituximab efficacy. (Blood. 2009; 113: 3765-3772)
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Rituximab dependent cytotoxicity by natural killer cells influence of fcgr3a polymorphism on the concentration effect relationship
2004Co-Authors: Sebastien Dallozzo, Guillaume Cartron, Herve Watier, Pierre Bardos, Gilles Paintaud, Sophie Tartas, Philippe Colombat, Gilles ThibaultAbstract:The FCGR3A gene dimorphism generates two allotypes: FcgammaRIIIa-158V and FcgammaRIIIa-158F. The genotype homozygous for FcgammaRIIIa-158V (VV) is associated with higher clinical response to Rituximab, a chimeric anti-CD20 IgG1 used in the treatment of B lymphoproliferative malignancies. Our objective was to determine whether this genetic association relates to Rituximab-dependent cytotoxicity mediated by FcgammaRIIIa/CD16a+ cells. The number of CD16+ circulating monocytes, T cells, and natural killer (NK) cells in 54 donors was first shown to be unrelated to FCGR3A polymorphism. We then demonstrated that FcgammaRIIIa-158V displays higher affinity for Rituximab than FcgammaRIIIa-158F by comparing Rituximab concentrations inhibiting the binding of 3G8 mAb (anti-CD16) with VV NK cells and NK cells homozygous for FcgammaRIIIa-158F (FF). VV and FF NK cells killed Daudi cells similarly after FcgammaRIIIa engagement by saturating concentrations of Rituximab or 3G8. However, the Rituximab concentration resulting in 50% lysis (EC(50)) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors (on average 0.00096 and 0.00402 microg/ml, respectively, P = 0.0043). Finally, the functional difference between VV and FF NK cells was restricted to Rituximab concentrations weakly sensitizing CD20. This study supports the conclusion that FCGR3A genotype is associated with response to Rituximab because it affects the relationship between Rituximab concentration and NK cell-mediated lysis of CD20+ cells. Rituximab administration could therefore be adjusted according to FCGR3A genotype.
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Rituximab dependent cytotoxicity by natural killer cells influence of fcgr3a polymorphism on the concentration effect relationship
2004Co-Authors: Sebastien Dallozzo, Guillaume Cartron, Herve Watier, Gilles Paintaud, Sophie Tartas, Philippe Colombat, P Bardos, Gilles ThibaultAbstract:The FCGR3A gene dimorphism generates two allotypes: FcγRIIIa-158V and FcγRIIIa-158F. The genotype homozygous for FcγRIIIa-158V (VV) is associated with higher clinical response to Rituximab, a chimeric anti-CD20 IgG1 used in the treatment of B lymphoproliferative malignancies. Our objective was to determine whether this genetic association relates to Rituximab-dependent cytotoxicity mediated by FcγRIIIa/CD16a+ cells. The number of CD16+ circulating monocytes, T cells, and natural killer (NK) cells in 54 donors was first shown to be unrelated to FCGR3A polymorphism. We then demonstrated that FcγRIIIa-158V displays higher affinity for Rituximab than FcγRIIIa-158F by comparing Rituximab concentrations inhibiting the binding of 3G8 mAb (anti-CD16) with VV NK cells and NK cells homozygous for FcγRIIIa-158F (FF). VV and FF NK cells killed Daudi cells similarly after FcγRIIIa engagement by saturating concentrations of Rituximab or 3G8. However, the Rituximab concentration resulting in 50% lysis (EC50) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors (on average 0.00096 and 0.00402 μg/ml, respectively, P = 0.0043). Finally, the functional difference between VV and FF NK cells was restricted to Rituximab concentrations weakly sensitizing CD20. This study supports the conclusion that FCGR3A genotype is associated with response to Rituximab because it affects the relationship between Rituximab concentration and NK cell-mediated lysis of CD20+ cells. Rituximab administration could therefore be adjusted according to FCGR3A genotype.
John D Hainsworth - One of the best experts on this subject based on the ideXlab platform.
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maximizing therapeutic benefit of Rituximab maintenance therapy versus re treatment at progression in patients with indolent non hodgkin s lymphoma a randomized phase ii trial of the minnie pearl cancer research network
2005Co-Authors: John D Hainsworth, Sharlene Litchy, Don W Shaffer, Van L Lackey, Manuel Grimaldi, Anthony F GrecoAbstract:Purpose To compare the benefit of maintenance Rituximab therapy versus Rituximab re-treatment at progression in patients with previously treated indolent non-Hodgkin's lymphoma. Patients and Methods Between June 1998 and August 2002, 114 patients who had received previous chemotherapy for indolent non-Hodgkin's lymphoma were treated with a standard 4-week course of Rituximab. Patients with objective response or stable disease were randomly assigned to receive either maintenance Rituximab therapy (standard 4-week courses administered at 6-month intervals) or Rituximab re-treatment at the time of lymphoma progression. The duration of Rituximab benefit was measured from the date of first Rituximab treatment until the date other treatment was required. Results Ninety (79%) of 114 patients had objective response or stable disease after initial Rituximab treatment, and were randomly assigned to treatment. Progression-free survival was prolonged in the maintenance group (31.3 v 7.4 months; P = .007). Final overa...
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Rituximab as first line and maintenance therapy for patients with indolent non hodgkin s lymphoma
2002Co-Authors: John D Hainsworth, Sharlene Litchy, Howard A Burris, Daniel C Scullin, Steven W Corso, Denise A Yardley, Lisa H Morrissey, Anthony F GrecoAbstract:PURPOSE: To evaluate response to single-agent Rituximab in patients with indolent non-Hodgkin’s lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance Rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line Rituximab therapy. PATIENTS AND METHODS: Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received Rituximab 375 mg/m2 intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance Rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four Rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months. RESULTS: Sixty patients (97%) completed the first 4-week course of Rituximab and were assessable for...
Gilles Thibault - One of the best experts on this subject based on the ideXlab platform.
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Rituximab dependent cytotoxicity by natural killer cells influence of fcgr3a polymorphism on the concentration effect relationship
2004Co-Authors: Sebastien Dallozzo, Guillaume Cartron, Herve Watier, Pierre Bardos, Gilles Paintaud, Sophie Tartas, Philippe Colombat, Gilles ThibaultAbstract:The FCGR3A gene dimorphism generates two allotypes: FcgammaRIIIa-158V and FcgammaRIIIa-158F. The genotype homozygous for FcgammaRIIIa-158V (VV) is associated with higher clinical response to Rituximab, a chimeric anti-CD20 IgG1 used in the treatment of B lymphoproliferative malignancies. Our objective was to determine whether this genetic association relates to Rituximab-dependent cytotoxicity mediated by FcgammaRIIIa/CD16a+ cells. The number of CD16+ circulating monocytes, T cells, and natural killer (NK) cells in 54 donors was first shown to be unrelated to FCGR3A polymorphism. We then demonstrated that FcgammaRIIIa-158V displays higher affinity for Rituximab than FcgammaRIIIa-158F by comparing Rituximab concentrations inhibiting the binding of 3G8 mAb (anti-CD16) with VV NK cells and NK cells homozygous for FcgammaRIIIa-158F (FF). VV and FF NK cells killed Daudi cells similarly after FcgammaRIIIa engagement by saturating concentrations of Rituximab or 3G8. However, the Rituximab concentration resulting in 50% lysis (EC(50)) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors (on average 0.00096 and 0.00402 microg/ml, respectively, P = 0.0043). Finally, the functional difference between VV and FF NK cells was restricted to Rituximab concentrations weakly sensitizing CD20. This study supports the conclusion that FCGR3A genotype is associated with response to Rituximab because it affects the relationship between Rituximab concentration and NK cell-mediated lysis of CD20+ cells. Rituximab administration could therefore be adjusted according to FCGR3A genotype.
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Rituximab dependent cytotoxicity by natural killer cells influence of fcgr3a polymorphism on the concentration effect relationship
2004Co-Authors: Sebastien Dallozzo, Guillaume Cartron, Herve Watier, Gilles Paintaud, Sophie Tartas, Philippe Colombat, P Bardos, Gilles ThibaultAbstract:The FCGR3A gene dimorphism generates two allotypes: FcγRIIIa-158V and FcγRIIIa-158F. The genotype homozygous for FcγRIIIa-158V (VV) is associated with higher clinical response to Rituximab, a chimeric anti-CD20 IgG1 used in the treatment of B lymphoproliferative malignancies. Our objective was to determine whether this genetic association relates to Rituximab-dependent cytotoxicity mediated by FcγRIIIa/CD16a+ cells. The number of CD16+ circulating monocytes, T cells, and natural killer (NK) cells in 54 donors was first shown to be unrelated to FCGR3A polymorphism. We then demonstrated that FcγRIIIa-158V displays higher affinity for Rituximab than FcγRIIIa-158F by comparing Rituximab concentrations inhibiting the binding of 3G8 mAb (anti-CD16) with VV NK cells and NK cells homozygous for FcγRIIIa-158F (FF). VV and FF NK cells killed Daudi cells similarly after FcγRIIIa engagement by saturating concentrations of Rituximab or 3G8. However, the Rituximab concentration resulting in 50% lysis (EC50) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors (on average 0.00096 and 0.00402 μg/ml, respectively, P = 0.0043). Finally, the functional difference between VV and FF NK cells was restricted to Rituximab concentrations weakly sensitizing CD20. This study supports the conclusion that FCGR3A genotype is associated with response to Rituximab because it affects the relationship between Rituximab concentration and NK cell-mediated lysis of CD20+ cells. Rituximab administration could therefore be adjusted according to FCGR3A genotype.
Anna Schuh - One of the best experts on this subject based on the ideXlab platform.
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Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia primary analysis of the randomized open label mable study
2018Co-Authors: Annesophie Michallet, Melih Aktan, Wolfgang Hiddemann, Osman Ilhan, Peter L Johansson, Kamel Laribi, Balkis Meddeb, Carol Moreno, Joao Raposo, Anna SchuhAbstract:MABLE investigated the efficacy and safety of Rituximab plus bendamustine or Rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received Rituximab plus bendamustine or Rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (Rituximab plus bendamustine, n=178; Rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (Rituximab plus bendamustine, 24%; Rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (Rituximab plus bendamustine, 40 months; Rituximab plus chlorambucil, 30 months; P=0.003) were higher with Rituximab plus bendamustine than Rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with Rituximab plus bendamustine than Rituximab plus chlorambucil (66% vs. 36%). Overall adverse event incidence was similar (Rituximab plus bendamustine, 98%; Rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia.
