160 results on '"Nelemans P"'
Search Results
2. Predictive Value of Minimal Residual Disease on Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results from the European MCL Elderly Trial
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Hoster, Eva, Delfau, Marie-Helene, Macintyre, Elizabeth A., Jiang, Linmiao, Stilgenbauer, Stephan, Vehling-Kaiser, Ursula, Salles, Gilles, Thieblemont, Catherine, Tilly, Hervé, Kanz, Lothar, Feugier, Pierre, Huebel, Kai, Schmidt, Christian, Ribrag, Vincent, Kluin-Nelemans, Hanneke, Dreyling, Martin, and Pott, Christiane
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- 2022
- Full Text
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3. LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome
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Thurner, Lorenz, Fadle, Natalie, Bittenbring, Jörg Thomas, Regitz, Evi, Schuck, Rita, Cetin, Onur, Stuhr, Ariane, Rixecker, Torben, Murawski, Niels, Poeschel, Viola, Kaddu-Mulindwa, Dominic, Preuss, Klaus-Dieter, Stilgenbauer, Stephan, Hermine, Olivier, Kluin-Nelemans, Hanneke C., Hartmann, Sylvia, Dreyling, Martin, Pott, Christiane, Bewarder, Moritz, and Hoster, Eva
- Abstract
Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain–restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P = .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index–adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P = .0083) and for OS of 0.47 (95% CI 0.24-0.94, P = .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients.
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- 2021
- Full Text
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4. LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome
- Author
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Thurner, Lorenz, Fadle, Natalie, Bittenbring, Jörg Thomas, Regitz, Evi, Schuck, Rita, Cetin, Onur, Stuhr, Ariane, Rixecker, Torben, Murawski, Niels, Poeschel, Viola, Kaddu-Mulindwa, Dominic, Preuss, Klaus-Dieter, Stilgenbauer, Stephan, Hermine, Olivier, Kluin-Nelemans, Hanneke C., Hartmann, Sylvia, Dreyling, Martin, Pott, Christiane, Bewarder, Moritz, and Hoster, Eva
- Abstract
Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain–restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P= .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index–adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P= .0083) and for OS of 0.47 (95% CI 0.24-0.94, P= .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients.
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- 2021
- Full Text
- View/download PDF
5. Induction and Maintenance Therapy in Elderly Patients with Mantle Cell Lymphoma: Double-Randomized MCL R2 Elderly Clinical Trial By the European Mantle Cell Lymphoma Network
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Ribrag, Vincent, Safar, Violaine, Kluin-Nelemans, Hanneke, Oberic, Lucie, Feugier, Pierre, Casasnovas, Olivier, Thieblemont, Catherine, Daguindau, Nicolas, Damaj, Gandhi Laurent, Hoster, Eva, Fischer von Weikersthal, Ludwig, Hänel, Mathias, Andre, Marc, Da Silva, Maria Gomes, Niebla, Ana Marín, Taszner, Michal, Walewski, Jan, Boersma, Rinske, Delfau-Larue, Marie-Helene, Le Gouill, Steven, and Dreyling, Martin
- Abstract
Background:Mantle cell lymphoma (MCL) formally remains an incurable disease. Recent trials in younger patients have demonstrated the benefit of a cytarabin-containing induction (Hermine, JCO 2022) and a rituximab (Le Gouill, NEJM 2017) as well as a lenalidomide maintenance (Ladetto, Lancet Haematol 2021). The MCL-R2 elderly trial investigated whether an induction with intermediate dose of cytarabine improves long term outcome over R-CHOP alone in elderly patients (>60 yrs). In addition, responders to induction therapy were randomized between a 2 year maintenance with rituximab-lenalidomide (R2) compared to rituximab alone. Here, we present the results of the 2 randomizations.
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- 2023
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6. Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL Network
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Aukema, Sietse M., Hoster, Eva, Rosenwald, Andreas, Canoni, Danielle, Delfau-Larue, Marie-Hélène, Rymkiewicz, Grzegorz, Thorns, Christoph, Hartmann, Sylvia, Kluin-Nelemans, Hanneke, Hermine, Olivier, Dreyling, Martin, and Klapper, Wolfram
- Abstract
Currently, prediction of time to treatment failure (TTF) and overall survival (OS) in mantle cell lymphoma (MCL) is based on the clinical factors included in the Mantle Cell Lymphoma International Prognostic Index (MIPI), and proliferation is assessed by Ki67. However, TP53 and SOX11 immunohistochemistry might improve risk stratification. We performed SOX11 and TP53 immunohistochemistry on the so far largest published cohort of lymphoma specimens (n = 365). All patients were treated in prospective trials of the European MCL Network. In multivariate analyses, including MIPI and Ki67, SOX11 expression was not associated with TTF, but patients with low SOX11 expression had shorter OS. On the contrary, high TP53 expression was a strong predictor of TTF and inferior OS compared with low TP53 expression in univariate and multivariate analyses adjusting for MIPI score and Ki-67 index (hazard ratio [HR], 2.0; P = .0054 for TTF, and HR, 2.1; P = .068 for OS). In particular, patients with high TP53 expression (>50% positive lymphoma cells) had a shorter TTF and poor OS independent of both MIPI score and Ki-67 index. Thus, TP53 immunohistochemistry is a suitable test for routine diagnostic practice to assess MCL prognosis.
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- 2018
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7. Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL Network
- Author
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Aukema, Sietse M., Hoster, Eva, Rosenwald, Andreas, Canoni, Danielle, Delfau-Larue, Marie-Hélène, Rymkiewicz, Grzegorz, Thorns, Christoph, Hartmann, Sylvia, Kluin-Nelemans, Hanneke, Hermine, Olivier, Dreyling, Martin, and Klapper, Wolfram
- Abstract
Currently, prediction of time to treatment failure (TTF) and overall survival (OS) in mantle cell lymphoma (MCL) is based on the clinical factors included in the Mantle Cell Lymphoma International Prognostic Index (MIPI), and proliferation is assessed by Ki67. However, TP53 and SOX11 immunohistochemistry might improve risk stratification. We performed SOX11 and TP53 immunohistochemistry on the so far largest published cohort of lymphoma specimens (n = 365). All patients were treated in prospective trials of the European MCL Network. In multivariate analyses, including MIPI and Ki67, SOX11 expression was not associated with TTF, but patients with low SOX11 expression had shorter OS. On the contrary, high TP53 expression was a strong predictor of TTF and inferior OS compared with low TP53 expression in univariate and multivariate analyses adjusting for MIPI score and Ki-67 index (hazard ratio [HR], 2.0; P= .0054 for TTF, and HR, 2.1; P= .068 for OS). In particular, patients with high TP53 expression (>50% positive lymphoma cells) had a shorter TTF and poor OS independent of both MIPI score and Ki-67 index. Thus, TP53 immunohistochemistry is a suitable test for routine diagnostic practice to assess MCL prognosis.
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- 2018
- Full Text
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8. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis
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Gotlib, Jason, Pardanani, Animesh, Akin, Cem, Reiter, Andreas, George, Tracy, Hermine, Olivier, Kluin-Nelemans, Hanneke, Hartmann, Karin, Sperr, Wolfgang R., Brockow, Knut, Schwartz, Lawrence B., Orfao, Alberto, DeAngelo, Daniel J., Arock, Michel, Sotlar, Karl, Horny, Hans-Peter, Metcalfe, Dean D., Escribano, Luis, Verstovsek, Srdan, Tefferi, Ayalew, and Valent, Peter
- Abstract
Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SMfor the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.
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- 2013
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9. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis
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Gotlib, Jason, Pardanani, Animesh, Akin, Cem, Reiter, Andreas, George, Tracy, Hermine, Olivier, Kluin-Nelemans, Hanneke, Hartmann, Karin, Sperr, Wolfgang R., Brockow, Knut, Schwartz, Lawrence B., Orfao, Alberto, DeAngelo, Daniel J., Arock, Michel, Sotlar, Karl, Horny, Hans-Peter, Metcalfe, Dean D., Escribano, Luis, Verstovsek, Srdan, Tefferi, Ayalew, and Valent, Peter
- Abstract
Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.
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- 2013
- Full Text
- View/download PDF
10. Double-hit B-cell lymphomas
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Aukema, Sietse M., Siebert, Reiner, Schuuring, Ed, van Imhoff, Gustaaf W., Kluin-Nelemans, Hanneke C., Boerma, Evert-Jan, and Kluin, Philip M.
- Abstract
In many B-cell lymphomas, chromosomal translocations are biologic and diagnostic hallmarks of disease. An intriguing subset is formed by the so-called double- hit (DH) lymphomas that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14;18)(q32;q21) involving BCL2. Recently, these lymphomas have received increased attention, which contributed to the introduction of a novel category of lymphomas in the 2008 WHO classification, “B cell lymphoma unclassifiable with features intermediate between DLBCL and BL.” In this review we explore the existing literature for the most recurrent types of DH B-cell lymphomas and the involved genes with their functions, as well as their pathology and clinical aspects including therapy and prognosis. The incidence of aggressive B-cell lymphomas other than Burkitt lymphoma with a MYC breakpoint and in particular a double hit is difficult to assess, because screening by methods like FISH has not been applied on large, unselected series, and the published cytogenetic data may be biased to specific categories of lymphomas. DH lymphomas have been classified heterogeneously but mostly as DLBCL, the majority having a germinal center phenotype and expression of BCL2. Patients with DH lymphomas often present with poor prognostic parameters, including elevated LDH, bone marrow and CNS involvement, and a high IPI score. All studies on larger series of patients suggest a poor prognosis, also if treated with RCHOP or high-intensity treatment modalities. Importantly, this poor outcome cannot be accounted for by the mere presence of a MYC/8q24 breakpoint. Likely, the combination of MYC and BCL2 expression and/or a related high genomic complexity are more important. Compared to these DH lymphomas, BCL6+/MYC+ DH lymphomas are far less common, and in fact most of these cases represent BCL2+/BCL6+/MYC+ triple-hit lymphomas with involvement of BCL2 as well. CCND1+/MYC+ DH lymphomas with involvement of 11q13 may also be relatively frequent, the great majority being classified as aggressive variants of mantle cell lymphoma. This suggests that activation of MYC might be an important progression pathway in mantle cell lymphoma as well. Based on clinical significance and the fact that no other solid diagnostic tools are available to identify DH lymphomas, it seems advisable to test all diffuse large B-cell and related lymphomas for MYC and other breakpoints.
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- 2011
- Full Text
- View/download PDF
11. Double-hit B-cell lymphomas
- Author
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Aukema, Sietse M., Siebert, Reiner, Schuuring, Ed, van Imhoff, Gustaaf W., Kluin-Nelemans, Hanneke C., Boerma, Evert-Jan, and Kluin, Philip M.
- Abstract
In many B-cell lymphomas, chromosomal translocations are biologic and diagnostic hallmarks of disease. An intriguing subset is formed by the so-called double- hit (DH) lymphomas that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14;18)(q32;q21) involving BCL2. Recently, these lymphomas have received increased attention, which contributed to the introduction of a novel category of lymphomas in the 2008 WHO classification, “B cell lymphoma unclassifiable with features intermediate between DLBCL and BL.” In this review we explore the existing literature for the most recurrent types of DH B-cell lymphomas and the involved genes with their functions, as well as their pathology and clinical aspects including therapy and prognosis. The incidence of aggressive B-cell lymphomas other than Burkitt lymphoma with a MYCbreakpoint and in particular a double hit is difficult to assess, because screening by methods like FISH has not been applied on large, unselected series, and the published cytogenetic data may be biased to specific categories of lymphomas. DH lymphomas have been classified heterogeneously but mostly as DLBCL, the majority having a germinal center phenotype and expression of BCL2. Patients with DH lymphomas often present with poor prognostic parameters, including elevated LDH, bone marrow and CNS involvement, and a high IPI score. All studies on larger series of patients suggest a poor prognosis, also if treated with RCHOP or high-intensity treatment modalities. Importantly, this poor outcome cannot be accounted for by the mere presence of a MYC/8q24 breakpoint. Likely, the combination of MYC and BCL2 expression and/or a related high genomic complexity are more important. Compared to these DH lymphomas, BCL6+/MYC+DH lymphomas are far less common, and in fact most of these cases represent BCL2+/BCL6+/MYC+triple-hit lymphomas with involvement of BCL2as well. CCND1+/MYC+DH lymphomas with involvement of 11q13 may also be relatively frequent, the great majority being classified as aggressive variants of mantle cell lymphoma. This suggests that activation of MYCmight be an important progression pathway in mantle cell lymphoma as well. Based on clinical significance and the fact that no other solid diagnostic tools are available to identify DH lymphomas, it seems advisable to test all diffuse large B-cell and related lymphomas for MYCand other breakpoints.
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- 2011
- Full Text
- View/download PDF
12. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study
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Pott, Christiane, Hoster, Eva, Delfau-Larue, Marie-Helene, Beldjord, Kheira, Böttcher, Sebastian, Asnafi, Vahid, Plonquet, Anne, Siebert, Reiner, Callet-Bauchu, Evelyne, Andersen, Niels, van Dongen, Jacques J. M., Klapper, Wolfram, Berger, Françoise, Ribrag, Vincent, van Hoof, Achiel L., Trneny, Marek, Walewski, Jan, Dreger, Peter, Unterhalt, Michael, Hiddemann, Wolfgang, Kneba, Michael, Kluin-Nelemans, Hanneke C., Hermine, Olivier, Macintyre, Elizabeth, and Dreyling, Martin
- Abstract
The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209.
- Published
- 2010
- Full Text
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13. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study
- Author
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Pott, Christiane, Hoster, Eva, Delfau-Larue, Marie-Helene, Beldjord, Kheira, Böttcher, Sebastian, Asnafi, Vahid, Plonquet, Anne, Siebert, Reiner, Callet-Bauchu, Evelyne, Andersen, Niels, van Dongen, Jacques J.M., Klapper, Wolfram, Berger, Françoise, Ribrag, Vincent, van Hoof, Achiel L., Trneny, Marek, Walewski, Jan, Dreger, Peter, Unterhalt, Michael, Hiddemann, Wolfgang, Kneba, Michael, Kluin-Nelemans, Hanneke C., Hermine, Olivier, Macintyre, Elizabeth, and Dreyling, Martin
- Abstract
The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P= .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P= .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P= .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P= .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P= .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.govas #NCT00209222 and #NCT00209209.
- Published
- 2010
- Full Text
- View/download PDF
14. Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial
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Ribrag, Vincent, Safar, Violaine, Kluin-Nelemans, Hanneke, Oberic, Lucie, Feugier, Pierre, Casasnovas, Olivier, Thieblemont, Catherine, Daguindau, Nicolas, Damaj, Gandhi Laurent, Klapper, Wolfram, Hoster, Eva, Fischer von Weikersthal, Ludwig, Haenel, Mathias, André, Marc, Gomes da Silva, Maria, Carcinero, Fernando, Marin-Niebla, Ana, Taszner, Michal, Walewski, Jan, Boersma, Rinske, Houtenbos, Ilse, Delfau-Larue, Marie-Helene, Le Gouill, Steven, and Dreyling, Martin H.
- Abstract
Background:Mantle cell lymphoma (MCL) formally remains an incurable disease. After immunochemotherapy induction, rituximab (R) maintenance can prolong remission duration, but most patients are highly exposed to relapse. The chemotherapy-free combination of lenalidomide and rituximab combo (R2) has demonstrated its activity in MCL, but has never been used as maintenance after immunochemotherapy and never been compared to RM. In the MCL R2 Elderly clinical trial (EUDRACT: 2012-002542-20), we studied different induction regimens and randomized R and R2 maintenance in responders to first-line induction. Here the results of the maintenance phase are reported.
- Published
- 2021
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15. Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial
- Author
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Ribrag, Vincent, Safar, Violaine, Kluin-Nelemans, Hanneke, Oberic, Lucie, Feugier, Pierre, Casasnovas, Olivier, Thieblemont, Catherine, Daguindau, Nicolas, Damaj, Gandhi Laurent, Klapper, Wolfram, Hoster, Eva, Fischer von Weikersthal, Ludwig, Haenel, Mathias, André, Marc, Gomes da Silva, Maria, Carcinero, Fernando, Marin-Niebla, Ana, Taszner, Michal, Walewski, Jan, Boersma, Rinske, Houtenbos, Ilse, Delfau-Larue, Marie-Helene, Le Gouill, Steven, and Dreyling, Martin H.
- Abstract
Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Argen-X: Research Funding; Astex Pharmaceuticals: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Safar: roche: Consultancy, Honoraria; novartis: Consultancy, Honoraria. Oberic: celgene: Consultancy, Honoraria; janssen: Consultancy, Honoraria; takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria; gilead: Consultancy, Honoraria. Feugier: Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Casasnovas: Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Gilead/Kite: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; ROCHE: Consultancy, Research Funding. Thieblemont: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Damaj: takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria. Klapper: Takeda: Consultancy, Research Funding; Regeneron: Consultancy, Research Funding; Amgen: Research Funding; Roche: Consultancy, Research Funding. Haenel: GSK: Consultancy; Jazz: Consultancy, Honoraria; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. André: Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Roche: Other: Travel/accomodation/expenses, Research Funding; Johnson & Johnson: Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Gomes da Silva: roche: Consultancy, Honoraria; gilead: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; novartis: Consultancy, Honoraria; az: Research Funding. Marin-Niebla: Janssen: Consultancy, Honoraria, Other: travel; Roche: Honoraria; Takeda: Consultancy, Honoraria, Other: travel; Kiowa Kirin: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Taszner: Roche, Takeda: Consultancy, Other: Travel. Walewski: GSK: Research Funding; roche: Honoraria, Research Funding, Speakers Bureau; novartis: Honoraria, Research Funding; takeda: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; gilead: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seervier: Consultancy, Honoraria. Dreyling: Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau.
- Published
- 2021
- Full Text
- View/download PDF
16. Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia
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Deenik, Wendy, van der Holt, Bronno, Verhoef, Gregor E. G., Smit, Willem M., Kersten, Marie J., Kluin-Nelemans, Hanneke C., Verdonck, Leo F., Ferrant, Augustin, Schattenberg, Anton V. M. B., Janssen, Jeroen J. W. M., Sonneveld, Pieter, van Marwijk Kooy, Marinus, Wittebol, Shulamit, Willemze, Roelof, Wijermans, Pierre W., Westveer, Petra H. M., Beverloo, H. Berna, Valk, Peter, Löwenberg, Bob, Ossenkoppele, Gert J., and Cornelissen, Jan J.
- Abstract
The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m2) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m2). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.
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- 2008
- Full Text
- View/download PDF
17. Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia
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Deenik, Wendy, van der Holt, Bronno, Verhoef, Gregor E.G., Smit, Willem M., Kersten, Marie J., Kluin-Nelemans, Hanneke C., Verdonck, Leo F., Ferrant, Augustin, Schattenberg, Anton V. M.B., Janssen, Jeroen J. W.M., Sonneveld, Pieter, van Marwijk Kooy, Marinus, Wittebol, Shulamit, Willemze, Roelof, Wijermans, Pierre W., Westveer, Petra H.M., Beverloo, H. Berna, Valk, Peter, Löwenberg, Bob, Ossenkoppele, Gert J., and Cornelissen, Jan J.
- Abstract
The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m2or 1000 mg/m2days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m2) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m2). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nlas no. CKTO-2001-03.
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- 2008
- Full Text
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18. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma
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Hoster, Eva, Dreyling, Martin, Klapper, Wolfram, Gisselbrecht, Christian, van Hoof, Achiel, Kluin-Nelemans, Hanneke C., Pfreundschuh, Michael, Reiser, Marcel, Metzner, Bernd, Einsele, Hermann, Peter, Norma, Jung, Wolfram, Wörmann, Bernhard, Ludwig, Wolf-Dieter, Dührsen, Ulrich, Eimermacher, Hartmut, Wandt, Hannes, Hasford, Joerg, Hiddemann, Wolfgang, and Unterhalt, Michael
- Abstract
There is no generally established prognostic index for patients with mantle cell lymphoma (MCL), because the International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) have been developed for diffuse large cell and follicular lymphoma patients, respectively. Using data of 455 advanced stage MCL patients treated within 3 clinical trials, we examined the prognostic relevance of IPI and FLIPI and derived a new prognostic index (MCL international prognostic index, MIPI) of overall survival (OS). Statistical methods included Kaplan-Meier estimates and the log-rank test for evaluating IPI and FLIPI and multiple Cox regression for developing the MIPI. IPI and FLIPI showed poor separation of survival curves. According to the MIPI, patients were classified into low risk (44% of patients, median OS not reached), intermediate risk (35%, 51 months), and high risk groups (21%, 29 months), based on the 4 independent prognostic factors: age, performance status, lactate dehydrogenase (LDH), and leukocyte count. Cell proliferation (Ki-67) was exploratively analyzed as an important biologic marker and showed strong additional prognostic relevance. The MIPI is the first prognostic index particularly suited for MCL patients and may serve as an important tool to facilitate risk-adapted treatment decisions in patients with advanced stage MCL.
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- 2008
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- View/download PDF
19. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma
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Hoster, Eva, Dreyling, Martin, Klapper, Wolfram, Gisselbrecht, Christian, van Hoof, Achiel, Kluin-Nelemans, Hanneke C., Pfreundschuh, Michael, Reiser, Marcel, Metzner, Bernd, Einsele, Hermann, Peter, Norma, Jung, Wolfram, Wörmann, Bernhard, Ludwig, Wolf-Dieter, Dührsen, Ulrich, Eimermacher, Hartmut, Wandt, Hannes, Hasford, Joerg, Hiddemann, Wolfgang, and Unterhalt, Michael
- Abstract
There is no generally established prognostic index for patients with mantle cell lymphoma (MCL), because the International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) have been developed for diffuse large cell and follicular lymphoma patients, respectively. Using data of 455 advanced stage MCL patients treated within 3 clinical trials, we examined the prognostic relevance of IPI and FLIPI and derived a new prognostic index (MCL international prognostic index, MIPI) of overall survival (OS). Statistical methods included Kaplan-Meier estimates and the log-rank test for evaluating IPI and FLIPI and multiple Cox regression for developing the MIPI. IPI and FLIPI showed poor separation of survival curves. According to the MIPI, patients were classified into low risk (44% of patients, median OS not reached), intermediate risk (35%, 51 months), and high risk groups (21%, 29 months), based on the 4 independent prognostic factors: age, performance status, lactate dehydrogenase (LDH), and leukocyte count. Cell proliferation (Ki-67) was exploratively analyzed as an important biologic marker and showed strong additional prognostic relevance. The MIPI is the first prognostic index particularly suited for MCL patients and may serve as an important tool to facilitate risk-adapted treatment decisions in patients with advanced stage MCL.
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- 2008
- Full Text
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20. Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma
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Moser, Elizabeth C., Noordijk, Evert M., van Leeuwen, Flora E., le Cessie, Saskia, Baars, Joke W., Thomas, José, Carde, Patrice, Meerwaldt, Jacobus H., van Glabbeke, Martine, and Kluin-Nelemans, Hanneke C.
- Abstract
Cardiovascular disease frequently occurs after lymphoma therapy, but it is common in the general population too. Therefore, risk estimation requires comparison to population-based rates. We calculated risk by standardized incidence ratios (SIRs) and absolute excess risks (AERs) per 10 000 person-years based on general population rates (Continuous Morbidity Registry Nijmegen) in 476 (Dutch and Belgian) patients with aggressive non-Hodgkin lymphoma (NHL) treated with at least 6 cycles of doxorubicin-based chemotherapy in 4 European Organization for Research on Treatment of Cancer (EORTC) trials (1980-1999). Cumulative incidence of cardiovascular disease, estimated in a competing risk model, was 12% at 5 years and 22% at 10 years (median follow-up, 8.4 years). Risk of chronic heart failure appeared markedly increased (SIR, 5.4; 95% CI, 4.1-6.9) with an AER of 208 excess cases per 10 000 person-years, whereas risk of coronary artery disease matched the general population (SIR, 1.2; 95% CI, 0.8-1.8; AER, 8 per 10 000 person-years). Risk of stroke was raised (SIR, 1.8; 95% CI, 1.1-2.4; AER, 15 per 10 000 person-years), especially after additional radiotherapy (> 40 Gy). Preexisting hypertension, NHL at young age, and salvage treatment increased risk of all cardiovascular events; the effect of radiotherapy was dose dependent. In conclusion, patients are at long-term high risk of chronic heart failure after NHL treatment and need therefore life-long monitoring. In contrast, risk of coronary artery disease appeared more age dependent than treatment related.
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- 2006
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21. Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma
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Moser, Elizabeth C., Noordijk, Evert M., van Leeuwen, Flora E., le Cessie, Saskia, Baars, Joke W., Thomas, José, Carde, Patrice, Meerwaldt, Jacobus H., van Glabbeke, Martine, and Kluin-Nelemans, Hanneke C.
- Abstract
Cardiovascular disease frequently occurs after lymphoma therapy, but it is common in the general population too. Therefore, risk estimation requires comparison to population-based rates. We calculated risk by standardized incidence ratios (SIRs) and absolute excess risks (AERs) per 10 000 person-years based on general population rates (Continuous Morbidity Registry Nijmegen) in 476 (Dutch and Belgian) patients with aggressive non-Hodgkin lymphoma (NHL) treated with at least 6 cycles of doxorubicin-based chemotherapy in 4 European Organization for Research on Treatment of Cancer (EORTC) trials (1980-1999). Cumulative incidence of cardiovascular disease, estimated in a competing risk model, was 12% at 5 years and 22% at 10 years (median follow-up, 8.4 years). Risk of chronic heart failure appeared markedly increased (SIR, 5.4; 95% CI, 4.1-6.9) with an AER of 208 excess cases per 10 000 person-years, whereas risk of coronary artery disease matched the general population (SIR, 1.2; 95% CI, 0.8-1.8; AER, 8 per 10 000 person-years). Risk of stroke was raised (SIR, 1.8; 95% CI, 1.1-2.4; AER, 15 per 10 000 person-years), especially after additional radiotherapy (> 40 Gy). Preexisting hypertension, NHL at young age, and salvage treatment increased risk of all cardiovascular events; the effect of radiotherapy was dose dependent. In conclusion, patients are at long-term high risk of chronic heart failure after NHL treatment and need therefore life-long monitoring. In contrast, risk of coronary artery disease appeared more age dependent than treatment related.
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- 2006
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22. Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas
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Muris, Jettie J.F., Cillessen, Saskia A.G.M., Vos, Wim, van Houdt, Inge S., Kummer, J.Alain, van Krieken, Johan H.J.M., Jiwa, N.Mehdi, Jansen, Patty M., Kluin-Nelemans, Hanneke C., Ossenkoppele, Gert J., Gundy, Chad, Meijer, Chris J.L.M., and Oudejans, Joost J.
- Abstract
We used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL.
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- 2005
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23. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network
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Dreyling, Martin, Lenz, Georg, Hoster, Eva, Van Hoof, Achiel, Gisselbrecht, Christian, Schmits, Rudolf, Metzner, Bernd, Truemper, Lorenz, Reiser, Marcel, Steinhauer, Hjalmar, Boiron, Jean-Michel, Boogaerts, Marc A., Aldaoud, Ali, Silingardi, Vittorio, Kluin-Nelemans, Hanneke C., Hasford, Joerg, Parwaresch, Reza, Unterhalt, Michael, and Hiddemann, Wolfgang
- Abstract
Mantle-cell lymphoma (MCL) is characterized by poor prognosis with a median survival of only 3 to 4 years. To improve clinical outcome, the European MCL Network initiated a randomized trial comparing consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT) to α-interferon maintenance (IFNα) in first remission. Patients 65 years of age or younger with advanced-stage MCL were assigned to ASCT or IFNα after achievement of complete or partial remission by a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like induction therapy. According to the International Prognostic Index (IPI), 43% of patients had a low-risk, 41% a low-intermediate, 11% a high-intermediate, and 6% a high-risk profile. Sixty-two of 122 patients proceeded to ASCT and 60 received IFNα. Patients in the ASCT arm experienced a significantly longer progression-free survival (PFS) with a median of 39 months compared with 17 months for patients in the IFNα arm (P = .0108). The 3-year overall survival (OS) was 83% after ASCT versus 77% in the IFN group (P = .18). Early consolidation by myeloablative radiochemotherapy followed by ASCT is feasible and results in a significant prolongation of PFS in advanced-stage MCL. Longer follow-up is needed to determine the effect on OS.
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- 2005
- Full Text
- View/download PDF
24. Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas
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Muris, Jettie J. F., Cillessen, Saskia A. G. M., Vos, Wim, van Houdt, Inge S., Kummer, J. Alain, van Krieken, Johan H. J. M., Jiwa, N. Mehdi, Jansen, Patty M., Kluin-Nelemans, Hanneke C., Ossenkoppele, Gert J., Gundy, Chad, Meijer, Chris J. L. M., and Oudejans, Joost J.
- Abstract
We used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL.
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- 2005
- Full Text
- View/download PDF
25. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network
- Author
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Dreyling, Martin, Lenz, Georg, Hoster, Eva, Van Hoof, Achiel, Gisselbrecht, Christian, Schmits, Rudolf, Metzner, Bernd, Truemper, Lorenz, Reiser, Marcel, Steinhauer, Hjalmar, Boiron, Jean-Michel, Boogaerts, Marc A., Aldaoud, Ali, Silingardi, Vittorio, Kluin-Nelemans, Hanneke C., Hasford, Joerg, Parwaresch, Reza, Unterhalt, Michael, and Hiddemann, Wolfgang
- Abstract
Mantle-cell lymphoma (MCL) is characterized by poor prognosis with a median survival of only 3 to 4 years. To improve clinical outcome, the European MCL Network initiated a randomized trial comparing consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT) to α-interferon maintenance (IFNα) in first remission. Patients 65 years of age or younger with advanced-stage MCL were assigned to ASCT or IFNα after achievement of complete or partial remission by a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like induction therapy. According to the International Prognostic Index (IPI), 43% of patients had a low-risk, 41% a low-intermediate, 11% a high-intermediate, and 6% a high-risk profile. Sixty-two of 122 patients proceeded to ASCT and 60 received IFNα. Patients in the ASCT arm experienced a significantly longer progression-free survival (PFS) with a median of 39 months compared with 17 months for patients in the IFNα arm (P= .0108). The 3-year overall survival (OS) was 83% after ASCT versus 77% in the IFN group (P= .18). Early consolidation by myeloablative radiochemotherapy followed by ASCT is feasible and results in a significant prolongation of PFS in advanced-stage MCL. Longer follow-up is needed to determine the effect on OS.
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- 2005
- Full Text
- View/download PDF
26. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus
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Brouwer, Jan-Leendert P., Bijl, Marc, Veeger, Nic J. G. M., Kluin-Nelemans, Hanneke C., and van der Meer, Jan
- Abstract
Systemic lupus erythematosus (SLE) is associated with an increased risk of venous (VTE) and arterial thromboembolism (ATE). Lupus anticoagulant (LA) and anticardiolipin antibodies (ACAs) are established risk factors. We assessed the contribution of deficiencies of antithrombin, protein C, total protein S, factor V Leiden, the prothrombin G20210A mutation and APC resistance, either alone or in various combinations with LA and/or ACAs, to the thrombotic risk in a cohort of 144 consecutive patients with SLE. Median follow-up was 12.7 years. VTE had occurred in 10% and ATE in 11% of patients. LA,ACAs, factor V Leiden, and the prothrombin mutation were identified as risk factors for VTE. Annual incidences of VTE were 2.01 (0.74-4.37) in patients with one of these disorders and 3.05 (0.63-8.93) in patients with 2 disorders. The risk of VTE was 20- and 30-fold higher, respectively, compared with the normal population. In contrast with LA and ACAs, thrombophilic disorders did not influence the risk of ATE. In conclusion, factor V Leiden and the prothrombin mutation contribute to the risk of VTE in patients with SLE, and potentiate this risk when one of these thrombophilic defects are combined with LA and/or ACAs.
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- 2004
- Full Text
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27. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus
- Author
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Brouwer, Jan-Leendert P., Bijl, Marc, Veeger, Nic J.G.M., Kluin-Nelemans, Hanneke C., and van der Meer, Jan
- Abstract
Systemic lupus erythematosus (SLE) is associated with an increased risk of venous (VTE) and arterial thromboembolism (ATE). Lupus anticoagulant (LA) and anticardiolipin antibodies (ACAs) are established risk factors. We assessed the contribution of deficiencies of antithrombin, protein C, total protein S, factor V Leiden, the prothrombin G20210A mutation and APC resistance, either alone or in various combinations with LA and/or ACAs, to the thrombotic risk in a cohort of 144 consecutive patients with SLE. Median follow-up was 12.7 years. VTE had occurred in 10% and ATE in 11% of patients. LA,ACAs, factor V Leiden, and the prothrombin mutation were identified as risk factors for VTE. Annual incidences of VTE were 2.01 (0.74-4.37) in patients with one of these disorders and 3.05 (0.63-8.93) in patients with 2 disorders. The risk of VTE was 20- and 30-fold higher, respectively, compared with the normal population. In contrast with LA and ACAs, thrombophilic disorders did not influence the risk of ATE. In conclusion, factor V Leiden and the prothrombin mutation contribute to the risk of VTE in patients with SLE, and potentiate this risk when one of these thrombophilic defects are combined with LA and/or ACAs.
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- 2004
- Full Text
- View/download PDF
28. Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups
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Kluin-Nelemans, Hanneke C., Buck, Georgina, le Cessie, Saskia, Richards, Sue, Beverloo, H. Berna, Falkenburg, J. H. Frederik, Littlewood, Tim, Muus, Petra, Bareford, David, van der Lelie, Hans, Green, Anthony R., Roozendaal, Klaas J., Milne, Alison E., Chapman, Claire S., and Shepherd, Patricia
- Abstract
The optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is unknown. Retrospective analyses suggest that low doses are as effective as high doses, with less toxicity and fewer patients abandoning the drug. The Dutch Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC) cooperative groups jointly performed randomized trials in newly diagnosed CML patients, comparing high-dose IFN (5 MIU/m2 daily) with low-dose (3 MIU, 5 times a week). Both arms allowed additional hydroxyurea to keep the white blood cell count lower than 5 × 109/L. Quality of life data were collected in a subset of patients. Between 1993 and 2001, 407 patients were randomized. At a median follow-up of 53 months, there were no significant differences in overall survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression-free survival, and complete hematologic or major cytogenetic responses. Fewer patients in the low-dose group abandoned IFN for reasons other than transplant or progressive disease (P = .002, 58% vs 72% at 5 years). Quality of life data showed comparable results in both arms for most factors. There is no evidence of benefit for high-dose IFN compared with low-dose for the treatment of CML. Therefore, when IFN is combined with other drugs, low-dose IFN is advised, to minimize toxicity and costs. (Blood. 2004;103:4408-4415)
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- 2004
- Full Text
- View/download PDF
29. Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups
- Author
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Kluin-Nelemans, Hanneke C., Buck, Georgina, le Cessie, Saskia, Richards, Sue, Beverloo, H. Berna, Falkenburg, J. H. Frederik, Littlewood, Tim, Muus, Petra, Bareford, David, van der Lelie, Hans, Green, Anthony R., Roozendaal, Klaas J., Milne, Alison E., Chapman, Claire S., and Shepherd, Patricia
- Abstract
The optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is unknown. Retrospective analyses suggest that low doses are as effective as high doses, with less toxicity and fewer patients abandoning the drug. The Dutch Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC) cooperative groups jointly performed randomized trials in newly diagnosed CML patients, comparing high-dose IFN (5 MIU/m2daily) with low-dose (3 MIU, 5 times a week). Both arms allowed additional hydroxyurea to keep the white blood cell count lower than 5 × 109/L. Quality of life data were collected in a subset of patients. Between 1993 and 2001, 407 patients were randomized. At a median follow-up of 53 months, there were no significant differences in overall survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression-free survival, and complete hematologic or major cytogenetic responses. Fewer patients in the low-dose group abandoned IFN for reasons other than transplant or progressive disease (P= .002, 58% vs 72% at 5 years). Quality of life data showed comparable results in both arms for most factors. There is no evidence of benefit for high-dose IFN compared with low-dose for the treatment of CML. Therefore, when IFN is combined with other drugs, low-dose IFN is advised, to minimize toxicity and costs. (Blood. 2004;103:4408-4415)
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- 2004
- Full Text
- View/download PDF
30. Cladribine therapy for systemic mastocytosis
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Kluin-Nelemans, Hanneke C., Oldhoff, J. Marja, van Doormaal, Jasper J., van 't Wout, Jan W., Verhoef, Gregor, Gerrits, Wim B. J., van Dobbenburgh, O. Aart, Pasmans, Suzanne G., and Fijnheer, Rob
- Abstract
Patients with systemic mastocytosis (SM) can suffer from disabling symptoms related to mast cell mediator release or mast cell infiltration, requiring mast cell eradication. In the present absence of any curative therapy, a recent case report describing the efficacy of cladribine showed promising results. In a pilot study, the efficacy of cladribine (0.10-0.13 mg/kg in a 2-hour infusion, days 1-5; repeated at 4-8 weeks until 6 cycles) was studied. Ten patients with SM with severe symptoms were treated. Four patients were classified as having indolent or smoldering mastocytosis, 3 as having aggressive systemic mastocytosis, and 3 as having SM with an accompanying hematologic malignancy. Nine patients received 6 courses, 1 patient stopped because of toxicodermia. All responded concerning signs, symptoms, and mast cell parameters (serum tryptase and urinary histamine metabolite excretion), although none achieved a complete remission. Prolonged follow-up is required, as response is ongoing in most cases. One patient relapsed within 11 months and showed a second response. Side effects were mainly related to bone marrow suppression. Single-agent cladribine is an effective and relatively safe treatment for severe systemic mastocytosis. The optimal dose and schedule need to be explored. (Blood. 2003;102:4270-4276)
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- 2003
- Full Text
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31. Cladribine therapy for systemic mastocytosis
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Kluin-Nelemans, Hanneke C., Oldhoff, J. Marja, van Doormaal, Jasper J., van 't Wout, Jan W., Verhoef, Gregor, Gerrits, Wim B.J., van Dobbenburgh, O. Aart, Pasmans, Suzanne G., and Fijnheer, Rob
- Abstract
Patients with systemic mastocytosis (SM) can suffer from disabling symptoms related to mast cell mediator release or mast cell infiltration, requiring mast cell eradication. In the present absence of any curative therapy, a recent case report describing the efficacy of cladribine showed promising results. In a pilot study, the efficacy of cladribine (0.10-0.13 mg/kg in a 2-hour infusion, days 1-5; repeated at 4-8 weeks until 6 cycles) was studied. Ten patients with SM with severe symptoms were treated. Four patients were classified as having indolent or smoldering mastocytosis, 3 as having aggressive systemic mastocytosis, and 3 as having SM with an accompanying hematologic malignancy. Nine patients received 6 courses, 1 patient stopped because of toxicodermia. All responded concerning signs, symptoms, and mast cell parameters (serum tryptase and urinary histamine metabolite excretion), although none achieved a complete remission. Prolonged follow-up is required, as response is ongoing in most cases. One patient relapsed within 11 months and showed a second response. Side effects were mainly related to bone marrow suppression. Single-agent cladribine is an effective and relatively safe treatment for severe systemic mastocytosis. The optimal dose and schedule need to be explored. (Blood. 2003;102:4270-4276)
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- 2003
- Full Text
- View/download PDF
32. Chronic myeloid leukemia and interferon-α: a study of complete cytogenetic responders
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Bonifazi, Francesca, de Vivo, Antonio, Rosti, Gianantonio, Guilhot, François, Guilhot, Joëlle, Trabacchi, Elena, Hehlmann, Rüdiger, Hochhaus, Andreas, Shepherd, Patricia C. A., Steegmann, Juan Luis, Kluin-Nelemans, Hanneke C., Thaler, Josef, Simonsson, Bengt, Louwagie, Andries, Reiffers, Josy, Mahon, François Xavier, Montefusco, Enrico, Alimena, Giuliana, Hasford, Joerg, Richards, Sue, Saglio, Giuseppe, Testoni, Nicoletta, Martinelli, Giovanni, Tura, Sante, and Baccarani, Michele
- Abstract
Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-α (IFN-α), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-α alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-α treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.
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- 2001
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33. Chronic myeloid leukemia and interferon-α: a study of complete cytogenetic responders
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Bonifazi, Francesca, de Vivo, Antonio, Rosti, Gianantonio, Guilhot, François, Guilhot, Joëlle, Trabacchi, Elena, Hehlmann, Rüdiger, Hochhaus, Andreas, Shepherd, Patricia C.A., Steegmann, Juan Luis, Kluin-Nelemans, Hanneke C., Thaler, Josef, Simonsson, Bengt, Louwagie, Andries, Reiffers, Josy, Mahon, François Xavier, Montefusco, Enrico, Alimena, Giuliana, Hasford, Joerg, Richards, Sue, Saglio, Giuseppe, Testoni, Nicoletta, Martinelli, Giovanni, Tura, Sante, Baccarani, Michele, and Leukemia, for the European Study Group on Interferon in Chronic Myeloid
- Abstract
Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-α (IFN-α), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-α alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-α treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.
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- 2001
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34. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura
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Portielje, Johanna E. A., Westendorp, Rudi G. J., Kluin-Nelemans, Hanneke C., and Brand, Anneke
- Abstract
To study outcomes of adults with idiopathic thrombocytopenic purpura (ITP), we performed a follow-up study in a cohort of 152 consecutive patients who were treated according to a well-defined algorithm. Long-term outcomes were determined relative to the response 2 years after diagnosis, because most (93%) patients who ultimately attained platelet counts above 30.0?×?109/L (30?000/µL) did so within this time frame. Complete follow-up for mortality could be studied in 99% of patients and for morbidity in 95% of patients, with a mean of 10.5 years. Within 2 years after diagnosis, 4 patients died, 2 were lost to follow-up, and 12 were reclassified as having secondary immune thrombocytopenia. Of the remaining 134 patients, 114 (85%) had obtained platelet counts above 30.0?×?109/L while all therapies had been discontinued. These patients had a long-term mortality risk equal to the general population. Twelve of 134 patients (9%), all with severe thrombocytopenia, had refractory disease and suffered a mortality risk of 4.2 (95% confidence interval, 1.7-10.0). Bleeding and infection equally contributed to the death of these patients. Another 8 patients (6%) had platelet counts above 30.0?×?109/L while on maintenance therapy. Similar to patients with refractory disease, these latter patients had considerably increased ITP-related hospital admissions, but mortality was only slightly higher than in the general population. In conclusion, most adults with ITP have a good outcome with infrequent hospital admissions and no excess mortality. The absence of gross morbidity and mortality in patients with moderate thrombocytopenia supports clinical practice refraining from further treatment.
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- 2001
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35. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura
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Portielje, Johanna E.A., Westendorp, Rudi G.J., Kluin-Nelemans, Hanneke C., and Brand, Anneke
- Abstract
To study outcomes of adults with idiopathic thrombocytopenic purpura (ITP), we performed a follow-up study in a cohort of 152 consecutive patients who were treated according to a well-defined algorithm. Long-term outcomes were determined relative to the response 2 years after diagnosis, because most (93%) patients who ultimately attained platelet counts above 30.0 × 109/L (30 000/μL) did so within this time frame. Complete follow-up for mortality could be studied in 99% of patients and for morbidity in 95% of patients, with a mean of 10.5 years. Within 2 years after diagnosis, 4 patients died, 2 were lost to follow-up, and 12 were reclassified as having secondary immune thrombocytopenia. Of the remaining 134 patients, 114 (85%) had obtained platelet counts above 30.0 × 109/L while all therapies had been discontinued. These patients had a long-term mortality risk equal to the general population. Twelve of 134 patients (9%), all with severe thrombocytopenia, had refractory disease and suffered a mortality risk of 4.2 (95% confidence interval, 1.7-10.0). Bleeding and infection equally contributed to the death of these patients. Another 8 patients (6%) had platelet counts above 30.0 × 109/L while on maintenance therapy. Similar to patients with refractory disease, these latter patients had considerably increased ITP-related hospital admissions, but mortality was only slightly higher than in the general population. In conclusion, most adults with ITP have a good outcome with infrequent hospital admissions and no excess mortality. The absence of gross morbidity and mortality in patients with moderate thrombocytopenia supports clinical practice refraining from further treatment.
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- 2001
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36. Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment With Leukemia-Reactive Cytotoxic T Lymphocytes
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Falkenburg, J.H. Frederik, Wafelman, Amon R., Joosten, Peter, Smit, Willem M., van Bergen, Cornelis A.M., Bongaerts, Rian, Lurvink, Ellie, van der Hoorn, Menno, Kluck, Petra, Landegent, James E., Kluin-Nelemans, Hanneke C., Fibbe, Willem E., and Willemze, Roel
- Abstract
Relapse of chronic myeloid leukemia (CML) in chronic phase after allogeneic stem cell transplantation (SCT) can be successfully treated by donor lymphocyte infusion (DLI). However, relapse of accelerated phase CML, blast crisis, or acute leukemia after allogeneic SCT are resistant to DLI in the majority of cases. In vitro-selected and expanded leukemia-reactive T-cell lines may be more effective in inducing an antileukemic response in vivo. To treat a patient with accelerated phase CML after allogeneic SCT, leukemia-reactive cytotoxic T-lymphocyte (CTL) lines were generated from her HLA-identical donor. Using a modification of a limiting dilution assay, T cells were isolated from the donor, selected based on their ability to inhibit the in vitro growth of CML progenitor cells, and subsequently expanded in vitro to generate CTL lines. Three CTL lines were generated that lysed the leukemic cells from the patient and inhibited the growth of leukemic progenitor cells. The CTL did not react with lymphocytes from donor or recipient and did not affect donor hematopoietic progenitor cells. The 3 leukemia-reactive CTL lines were infused at 5-week intervals at a cumulative dose of 3.2 × 109 CTL. Shortly after the third infusion, complete eradication of the leukemic cells was observed, as shown by cytogenetic analysis, fluorescence in situ hybridization, molecular analysis of BCR/ABL-mRNA, and chimerism studies. These results show that in vitro cultured leukemia-reactive CTL lines selected on their ability to inhibit the proliferation of leukemic progenitor cells in vitro can be successfully applied to treat accelerated phase CML after allogeneic SCT.
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- 1999
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37. Hairy Cell Leukemia-Specific Recognition by Multiple Autologous HLA-DQ or DP-Restricted T-Cell Clones
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van de Corput, Lisette, Kluin-Nelemans, Hanneke C., Kester, Michel G.D., Willemze, Roel, and Falkenburg, J.H. Frederik
- Abstract
We studied in patients with hairy cell leukemia (HCL) whether autoreactive T cells could be isolated with specific reactivity to the HCL cells. HCL cells were activated via triggering of CD40 on the cell membrane and used as stimulator cells to generate autologous T-cell clones. Two types of CD4+BV2+ T-cell clones with different CDR3 rearrangements and one type of CD4+BV8S3+ T-cell clone were generated from the spleen or blood. These clones specifically recognized the autologous HCL cells, without reactivity to autologous peripheral blood mononuclear cells (PBMC), phytohemagglutinin blasts, or Epstein-Barr virus–transformed B cells in a primed lymphocyte test. Blocking and panel studies using HCL cells from 11 other patients showed that recognition of the HCL cells by the BV2+ T cells was restricted by HLA-DQA1*03/DQB1*0301, and the BV8S3+ T cells were restricted by DPB1*04. The T-cell clones did not recognize DPB1*04+ or DQ3+ PBMC from healthy donors or DP/DQ matched malignant cells from patients with other hematologic malignancies, except for one patient with acute lymphoblastic leukemia. These HCL-specific T-cell clones may be used for the detection of an HCL-specific tumor antigen.
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- 1999
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38. Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment With Leukemia-Reactive Cytotoxic T Lymphocytes
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Falkenburg, J.H. Frederik, Wafelman, Amon R., Joosten, Peter, Smit, Willem M., van Bergen, Cornelis A.M., Bongaerts, Rian, Lurvink, Ellie, van der Hoorn, Menno, Kluck, Petra, Landegent, James E., Kluin-Nelemans, Hanneke C., Fibbe, Willem E., and Willemze, Roel
- Abstract
Relapse of chronic myeloid leukemia (CML) in chronic phase after allogeneic stem cell transplantation (SCT) can be successfully treated by donor lymphocyte infusion (DLI). However, relapse of accelerated phase CML, blast crisis, or acute leukemia after allogeneic SCT are resistant to DLI in the majority of cases. In vitro-selected and expanded leukemia-reactive T-cell lines may be more effective in inducing an antileukemic response in vivo. To treat a patient with accelerated phase CML after allogeneic SCT, leukemia-reactive cytotoxic T-lymphocyte (CTL) lines were generated from her HLA-identical donor. Using a modification of a limiting dilution assay, T cells were isolated from the donor, selected based on their ability to inhibit the in vitro growth of CML progenitor cells, and subsequently expanded in vitro to generate CTL lines. Three CTL lines were generated that lysed the leukemic cells from the patient and inhibited the growth of leukemic progenitor cells. The CTL did not react with lymphocytes from donor or recipient and did not affect donor hematopoietic progenitor cells. The 3 leukemia-reactive CTL lines were infused at 5-week intervals at a cumulative dose of 3.2 × 109CTL. Shortly after the third infusion, complete eradication of the leukemic cells was observed, as shown by cytogenetic analysis, fluorescence in situ hybridization, molecular analysis of BCR/ABL-mRNA, and chimerism studies. These results show that in vitro cultured leukemia-reactive CTL lines selected on their ability to inhibit the proliferation of leukemic progenitor cells in vitro can be successfully applied to treat accelerated phase CML after allogeneic SCT.
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- 1999
- Full Text
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39. Correction of Abnormal T-Cell Receptor Repertoire During Interferon-a Therapy in Patients With Hairy Cell Leukemia
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Kluin-Nelemans, Hanneke C., Kester, Michel G.D., van deCorput, Lisette, Boor, Patrick P.C., Landegent, Jim E., van Dongen, Jacques J.M., Willemze, Roel, and Falkenburg, J.H. Frederik
- Abstract
Patients with the B-cell malignancy hairy cell leukemia (HCL) exhibit a skewed T-cell repertoire with oligoclonal expression or absence of many members of the T-cell receptor (TCR) BV gene families. To evaluate whether interferon-a (IFN-a) therapy would not only restore normal hematopoiesis, but also the abnormal T-cell repertoire, we studied T lymphocytes from a cohort of HCL patients treated by IFN-a in the past, at initiation, and at several intervals up to 6 years of IFN-a treatment. The junctional regions from 22 TCRBV gene families were analyzed after polymerase chain reaction amplification of cDNA (RT-PCR) using family specific primers. In all seven patients improvement of the skewed T-cell repertoire was not seen until 2 years of treatment. It consisted of disappearance of oligoclonal subpopulations and (polyclonal) reappearance of absent TCRBV gene families. The RT-PCR results were correlated with the TCRBV protein expression using TCRBV-specific monoclonal antibodies. T lymphocytes from four patients with active HCL contained large expansions of particular TCRBV-expressing cells (up to 25% of the CD3+cells; 600 to 700/µL whole blood), which decreased during IFN-a therapy in both patients tested. Finally, restoration of the TCR repertoire matched normalization of the functional immune repertoire as measured by proliferative, helper, and cytotoxic T-lymphocyte precursor frequencies against major histocompatibility complex–unrelated individuals. In conclusion, oligoclonal bands of TCRBV gene families found by RT-PCR correspond with a dramatic increase in circulating T lymphocytes expressing the same TCRBV family. Moreover, IFN-a can restore the skewed T-cell repertoire and suppress persistent T-cell clones upon treatment of the accompanying malignancy.
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- 1998
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40. Hairy cell leukemia preferentially expresses the IgG3-subclass
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Kluin-Nelemans, HC, Krouwels, MM, Jansen, JH, Dijkstra, K, van Tol, MJ, den Ottolander, GJ, Dreef, EJ, and Kluin, PM
- Abstract
Surface IgG expression of 29 cases of hairy cell leukemia (HCL) was assessed using IgG-subclass-specific monoclonal and F(ab)'2 polyclonal antibodies. A marked preference for the IgG3 subclass was found, as 16 of 19 IgG-positive HCL's expressed IgG3. In 10 cases, IgG3 was concurrently expressed with other heavy chains. No preferential IgG3 expression was observed in 11 IgG-positive non-Hodgkin's lymphomas. The marked predominance of IgG3 in HCL suggests a deviation in heavy chain class switching that may be related to the characteristically very low expression of LFA-1 and ICAM-1 molecules on hairy cells, and hence a defect in T-cell hairy cell interaction.
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- 1990
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41. A Strong Expression of CD44-6v Correlates With Shorter Survival of Patients With Acute Myeloid Leukemia
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Legras, S., Gu¨nthert, U., Stauder, R., Curt, F., Oliferenko, S., Kluin-Nelemans, H.C., Marie, J.P., Proctor, S., Jasmin, C., and Smadja-Joffe, F.
- Abstract
CD44 is a ubiquitous cell-surface glycoprotein that displays many variant isoforms (CD44v) generated by alternative splicing of exons 2v to 10v. The expression of variant isoforms is highly restricted and correlated with specific processes, such as leukocyte activation and malignant transformation. We have herein studied CD44v expression in acute myeloid leukemia (AML) and, for comparison, in normal myelopoiesis. Protein expression of total CD44 and of CD44-3v, -6v, and -9v isoforms has been measured using specific monoclonal antibodies and flow cytometry. The composition of variant exon transcripts has been analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction followed by Southern hybridization with exon-specific probes. Our data show that (1) CD44-6v isoforms are expressed on 12.0% ± 2.5% of normal CD34+ cells; this expression is sharply upregulated through monopoiesis and, inversely, downregulated during granulopoiesis. Also, CD44-3v and CD44-9v isoforms are detected on 10% and 14% of normal monocytes, respectively. (2) Sixty-nine from a total of 95 AML patients display a variable proportion (range, 5% to 80%) of CD44-6v+ leukemic cells. (3) A shorter overall survival characterizes the group of AML patients displaying more than 20% of CD44-6v+ leukemic cells (8 months v 18 months, P?.02). These data suggest, for the first time, that the protein expression of CD44-6v containing isoforms may serve as a new prognostic factor in AML.
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- 1998
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42. Induction of CD11a/leukocyte function antigen-1 and CD54/intercellular adhesion molecule-1 on hairy cell leukemia cells is accompanied by enhanced susceptibility to T-cell but not lymphokine-activated killer- cell cytotoxicity [see comments]
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Jansen, JH, van der Harst, D, Wientjens, GJ, Kooy-Winkelaar, YM, Brand, A, Willemze, R, and Kluin-Nelemans, HC
- Abstract
Some B-cell neoplasms, including hairy cell leukemia (HCL), lack expression of the adhesion molecule leukocyte function antigen-1 (LFA- 1/CD11a). Additionally, HCL cells express relatively low amounts of intercellular adhesion molecule-1 (ICAM-1/CD54) and may therefore be an inappropriate target for recognition by T cells or lymphokine-activated killer (LAK) cells. We tested whether these molecules were inducible on HCL cells and if induction would lead to enhanced susceptibility to lysis by LAK cells or cytolytic T cells. CD11a expression was induced by incubation with interferon-alpha (IFN-alpha) or interleukin-4. CD54 was induced by culturing the cells irrespectively of the addition of cytokines. Expression of CD11a and CD54 did not enhance susceptibility to either autologous or allogeneous LAK cells. However, induction of these adhesion molecules was accompanied by enhanced susceptibility to lysis by cytotoxic T lymphocyte clones. This lysis could be reversed by the addition of anti-CD11a and anti-CD54 antibodies. Finally, we monitored the expression of CD11a and CD54 on HCL cells from patients during IFN-alpha therapy. In one of four patients monitored, we observed rapid in vivo induction of CD11a and CD54 on the leukemic cells during IFN-alpha therapy. These studies provide a model for studying immunosurveillance in HCL.
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- 1992
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43. Combined immunophenotyping and DNA in situ hybridization to study lineage involvement in patients with myelodysplastic syndromes
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Kibbelaar, RE, van Kamp, H, Dreef, EJ, de Groot-Swings, G, Kluin-Nelemans, JC, Beverstock, GC, Fibbe, WE, and Kluin, PM
- Abstract
Clonality of myeloid and lymphoid cell fractions obtained from peripheral blood (PB) or bone marrow (BM) of five patients with a myelodysplastic syndrome (MDS), was studied by combined immunophenotypic analysis and DNA in situ hybridization. This novel technique enables quantitative and direct analysis of cytogenetic alterations in nondividing cells of distinct cell lineages. Four patients with a trisomy 8 and one patient with a translocation (1;7) were studied. For cell lineage determination, antibodies specific for progenitor cells (CD34), myeloid cells (CD15), monocytes (63D3), T cells (CD3), and B cells (CD19,20,22) were used. In one patient with a trisomy 8, BM cells were available and the erythroid lineage could be studied. For detection of cytogenetic aberrations, we used chromosome- specific repetitive DNA probes. In three patients, all nonlymphoid cells carried the cytogenetic abnormality; in two patients, mosaicism within these lineages was suggested by the relative low numbers (35% to 55%) of aberrant cells. None of the T or B cells of the five patients carried the chromosomal aberrations. We conclude that combined immunophenotyping and in situ hybridization is a feasible technique to study lineage involvement. Our data suggest that the chromosomal aberrations studied in MDS are restricted to the myeloid lineages.
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- 1992
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44. Persistent clonal excess and skewed T-cell repertoire in T cells from patients with hairy cell leukemia
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Kluin-Nelemans, JC, Kester, MG, Melenhorst, JJ, Landegent, JE, van de Corput, L, Willemze, R, and Falkenburg, JH
- Abstract
Hairy cell leukemia (HCL) is characterized by a severe T-cell-mediated immune deficiency. At the same time, spontaneous T-cell activation is noted when splenic T cells are studied in vivo and in vitro. Therefore, we searched for oligoclonal T-cell populations in the blood and spleens of 25 patients with HCL using a T-cell receptor gamma-polymerase chain reaction (TCR gamma-PCR). Subsequently, in 6 patients, the CDR3 length and conformation from 22 different TCRBV subfamilies were analyzed after PCR amplification of cDNA using TCRBV subfamily-specific primers. T cells from 15 of 25 HCL patients showed clonal excess by the TCR gamma-PCR. In fluorescence-activated cell sorted T-cell subsets, more clonal bands were observed than in the unseparated T cells, with most of these in CD8+ subsets, but also in CD4+, CD3+ gamma/delta+, and a double-negative CD3+ alpha/beta+ subset. In other B-cell malignancies, 6 of 16 samples showed oligoclonal T cells, whereas only 2 of 18 normal spleen and blood samples showed abnormal bands. Analysis of the TCRBV subfamilies disclosed in all 6 HCL patients a markedly abnormal pattern, with many clonal bands in 5 to 15 subfamilies, and absent or abnormal weak patterns in another 1 to 8 subfamilies. In comparison, 6 normal samples (2 spleens and 4 blood samples) showed in only 1 blood donor 1 clonal band. Two patients with active HCL but without infections or treatment were tested several times during the course of the disease and showed a complete identical skewed T-cell repertoire with the same oligoclonal T-cell populations. In conclusion, T cells in the blood and spleen of HCL patients show impressive abnormalities with many oligoclonal T-cell populations and a very restricted and skewed TCRBV repertoire.
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- 1996
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45. Persistent Clonal Excess and Skewed T-Cell Repertoire in T Cells From Patients With Hairy Cell Leukemia
- Author
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Kluin-Nelemans, J.C., Kester, M.G.D., Melenhorst, J.J., Landegent, J.E., Corput, L. van de, Willemze, R., and Falkenburg, J.H.F.
- Abstract
Hairy cell leukemia (HCL) is characterized by a severe T-cell-mediated immune deficiency. At the same time, spontaneous T-cell activation is noted when splenic T cells are studied in vivo and in vitro. Therefore, we searched for oligoclonal T-cell populations in the blood and spleens of 25 patients with HCL using a T-cell receptor γ-polymerase chain reaction (TCRγ-PCR). Subsequently, in 6 patients, the CDR3 length and conformation from 22 different TCRBV subfamilies were analyzed after PCR amplification of cDNA using TCRBV subfamily-specific primers. T cells from 15 of 25 HCL patients showed clonal excess by the TCRγ-PCR. In fluorescence-activated cell sorted T-cell subsets, more clonal bands were observed than in the unseparated T cells, with most of these in CD8+subsets, but also in CD4+, CD3+γ/δ+, and a double-negative CD3+α/β+subset. In other B-cell malignancies, 6 of 16 samples showed oligoclonal T cells, whereas only 2 of 18 normal spleen and blood samples showed abnormal bands. Analysis of the TCRBV subfamilies disclosed in all 6 HCL patients a markedly abnormal pattern, with many clonal bands in 5 to 15 subfamilies, and absent or abnormal weak patterns in another 1 to 8 subfamilies. In comparison, 6 normal samples (2 spleens and 4 blood samples) showed in only 1 blood donor 1 clonal band. Two patients with active HCL but without infections or treatment were tested several times during the course of the disease and showed a complete identical skewed T-cell repertoire with the same oligoclonal T-cell populations. In conclusion, T cells in the blood and spleen of HCL patients show impressive abnormalities with many oligoclonal T-cell populations and a very restricted and skewed TCRBV repertoire.
- Published
- 1996
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46. Oncogene Rearrangements in Chronic B-Cell Leukemia
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Raghoebier, S., van Krieken, J.H.J.M., Kluin-Nelemans, J.C., Gillis, A., van Ommen, G.J.B., Ginsberg, A.M., Raffeld, M., and Kluin, Ph.M.
- Abstract
Forty-four B-chronic lymphocytic leukemias (CLL) were studied by Southern blot analysis using probes for the Ig genes and bcl-1, bcl-2 (major, minor and 5’ breakpoint region), bcl-3, c-myc, and retinoblastoma (Rb) loci. Eight cases had three or more rearranged JH bands, indicating oligoclonality, clonal evolution, or chromosomal translocation. One case had a rearrangement of the bcl-1 locus and three of the bcl-2locus. In the first case, comigration of the rearranged bcl-1 and JH sequences indicated a t(11;14)(q13;q32) translocation, which, in contrast to previously described cases, seems to be completely reciprocal. One case with a bcl-2rearrangement showed comigration of the bcl-2major breakpoint region and a rearranged JH band. This indicates a t(14;18) (q32;q21). The two other cases showed rearrangements of the bcl-25’ breakpoint region without apparent comigration. No rearrangements were detected of c-mycand bcl-3, located at chromosome 19, nor was a deletion of Rb found. All but three cases had CD5 expression. The exceptions included the t(11 ; 14) and the t(14; 18) cases. Our results confirm recent data on rearrangements at the 5’ site of bcl-2in CLL. Additionally, they corroborate the presumption that CD5-negative chronic B-cell leukemias should be considered apart from classical CLL.
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- 1991
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47. International Prognostic Index for aggressive non-Hodgkin's lymphoma is valid for all malignancy grades
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Hermans, J, Krol, AD, van Groningen, K, Kluin, PM, Kluin-Nelemans, JC, Kramer, MH, Noordijk, EM, Ong, F, and Wijermans, PW
- Abstract
An International Prognostic Index (IPI) for patients with aggressive non-Hodgkin's lymphoma (NHL) has recently been published. The IPI is based on pretreatment clinical characteristics and developed on clinical trial patients, classified as intermediate grade according to the Working Formulation (WF). We applied this IPI in a population-based registry of NHL patients. This registry does not have the restrictions that usually hold for patients in clinical trials, eg, with respect to age and performance status. Moreover, it covers all the three WF classes (low, intermediate, and high). The IPI turned out to be of prognostic value for response rate and survival in our unselected cohort of 744 patients, as well. In each of the three WF classes separately, the four IPI classes showed going from low to high substantially decreasing response rates and survival percentages. For our cohort of WF intermediate grade patients 5-year survival levels were lower in all four IPI classes (59%, 34%, 14%, and 10%, respectively), probably reflecting the selection of clinical trial patients in the original study (73%, 51%, 43%, and 26%).
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- 1995
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48. Essential differences in oncogene involvement between primary nodal and extranodal large cell lymphoma
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Raghoebier, S, Kramer, MH, van Krieken, JH, de Jong, D, Limpens, J, Kluin- Nelemans, JC, van Ommen, GJ, and Kluin, PM
- Abstract
Large cell lymphomas (LCLs) are heterogeneous in morphology, clinical presentation, and behavior. We studied 52 de novo LCLs of B-cell type for rearrangements of the bcl-2 and c-myc oncogenes by Southern blot analysis and related these data to the primary site of presentation, stage, and cytomorphology. Thirteen tumors had comigrating rearrangements of JH and bcl-2, indicative of a t(14;18). Far more primary nodal lymphomas than extranodal lymphomas carried a t(14;18) (40% v less than 5%). Additionally, almost all lymphomas with a t(14;18) versus 41% of the tumors without a bcl-2 rearrangement presented with lymphadenopathy. c-myc rearrangements were seen in 35% of the extranodal lymphomas and 5% of the nodal lymphomas. No differences were observed in bone marrow involvement and staging according to Ann Arbor. bcl-2 rearrangements were found in 50% of the LCLs with cleaved nuclei, whereas c-myc rearrangements were relatively frequent (25%) in the noncleaved subtype. Our data support the hypothesis that primary nodal and extranodal lymphomas have a different genetic origin.
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- 1991
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49. Oncogene rearrangements in chronic B-cell leukemia
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Raghoebier, S, van Krieken, JH, Kluin-Nelemans, JC, Gillis, A, van Ommen, GJ, Ginsberg, AM, Raffeld, M, and Kluin, PM
- Abstract
Forty-four B-chronic lymphocytic leukemias (CLL) were studied by Southern blot analysis using probes for the Ig genes and bcl-1, bcl-2 (major, minor and 5' breakpoint region), bcl-3, c-myc, and retinoblastoma (Rb) loci. Eight cases had three or more rearranged JH bands, indicating oligoclonality, clonal evolution, or chromosomal translocation. One case had a rearrangement of the bcl-1 locus and three of the bcl-2 locus. In the first case, comigration of the rearranged bcl-1 and JH sequences indicated a t(11;14)(q13;q32) translocation, which, in contrast to previously described cases, seems to be completely reciprocal. One case with a bcl-2 rearrangement showed comigration of the bcl-2 major breakpoint region and a rearranged JH band. This indicates a t(14;18) (q32;q21). The two other cases showed rearrangements of the bcl-2 5' breakpoint region without apparent comigration. No rearrangements were detected of c-myc and bcl-3, located at chromosome 19, nor was a deletion of Rb found. All but three cases had CD5 expression. The exceptions included the t(11;14) and the t(14;18) cases. Our results confirm recent data on rearrangements at the 5' site of bcl-2 in CLL. Additionally, they corroborate the presumption that CD5-negative chronic B-cell leukemias should be considered apart from classical CLL.
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- 1991
- Full Text
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50. Effects of herpes virus carrier status on peripheral T lymphocyte subsets
- Author
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Gratama, JW, Naipal, AM, Oosterveer, MA, Stijnen, T, Kluin-Nelemans, HC, Ginsel, LA, den Ottolander, GJ, Hekker, AC, D'Amaro, J, and van der Giessen, M
- Abstract
We studied the effects of herpes virus carrier status on peripheral blood T lymphocyte subsets in 334 healthy individuals. IgG-class antibodies against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella-zoster virus (VZV) were used as markers for the carrier status of those viruses. CMV carrier status was associated with significant increases in the numbers of some T cell subsets, whereas the carrier status of EBV, HSV, and VZV had no significant effects. The 159 CMV-seropositive individuals had higher numbers of HNK1+ T cells than did the 175 CMV-seronegative individuals [mean (SD), 292 (196)/microL v 164 (89)/microL, respectively], including the CD4+HNK1+ T cells [38 (48)/microL v 9 (13)/microL, respectively] and the CD8+HNK1+ T cells [166 (146)/microL v 73 (54)/microL, respectively]. Morphological and cytochemical studies showed that the expression of HNK1 by the CD4+ and CD8+ T cells was associated with the occurrence of azurophilic cytoplasmatic granules and a loss of nonspecific esterase activity. The numbers of CD4+HNK1+ and CD8+HNK1+ T cells increased proportionally to the levels of the IgG- class CMV antibody titers. We suggest that the increased numbers of CD4+HNK1+ and CD8+HNK1+ granular T cells in CMV carriers reflect the persistent interaction between CMV and the immune system of its hosts.
- Published
- 1987
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