315 results on '"Zander, P."'
Search Results
2. Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy
- Author
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Zucca, Emanuele, Rondeau, Stephanie, Vanazzi, Anna, Østenstad, Bjørn, Mey, Ulrich J. M., Rauch, Daniel, Wahlin, Björn E., Hitz, Felicitas, Hernberg, Micaela, Johansson, Ann-Sofie, de Nully Brown, Peter, Hagberg, Hans, Ferreri, Andrés J. M., Lohri, Andreas, Novak, Urban, Zander, Thilo, Bersvendsen, Hanne, Bargetzi, Mario, Mingrone, Walter, Krasniqi, Fatime, Dirnhofer, Stefan, Hayoz, Stefanie, Hawle, Hanne, Vilei, Simona Berardi, Ghielmini, Michele, and Kimby, Eva
- Abstract
The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (=90%). Toxicity grade =3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.
- Published
- 2019
- Full Text
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3. Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy
- Author
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Zucca, Emanuele, Rondeau, Stephanie, Vanazzi, Anna, Østenstad, Bjørn, Mey, Ulrich J.M., Rauch, Daniel, Wahlin, Björn E., Hitz, Felicitas, Hernberg, Micaela, Johansson, Ann-Sofie, de Nully Brown, Peter, Hagberg, Hans, Ferreri, Andrés J.M., Lohri, Andreas, Novak, Urban, Zander, Thilo, Bersvendsen, Hanne, Bargetzi, Mario, Mingrone, Walter, Krasniqi, Fatime, Dirnhofer, Stefan, Hayoz, Stefanie, Hawle, Hanne, Vilei, Simona Berardi, Ghielmini, Michele, and Kimby, Eva
- Abstract
The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.govas #NCT01307605.
- Published
- 2019
- Full Text
- View/download PDF
4. Promising activity of nelfinavir-bortezomib-dexamethasone in proteasome inhibitor–refractory multiple myeloma
- Author
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Driessen, Christoph, Müller, Rouven, Novak, Urban, Cantoni, Nathan, Betticher, Daniel, Mach, Nicolas, Rüfer, Axel, Mey, Ulrich, Samaras, Panagiotis, Ribi, Karin, Besse, Lenka, Besse, Andrej, Berset, Catherine, Rondeau, Stephanie, Hawle, Hanne, Hitz, Felicitas, Pabst, Thomas, and Zander, Thilo
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- 2018
- Full Text
- View/download PDF
5. Promising activity of nelfinavir-bortezomib-dexamethasone in proteasome inhibitor–refractory multiple myeloma
- Author
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Driessen, Christoph, Müller, Rouven, Novak, Urban, Cantoni, Nathan, Betticher, Daniel, Mach, Nicolas, Rüfer, Axel, Mey, Ulrich, Samaras, Panagiotis, Ribi, Karin, Besse, Lenka, Besse, Andrej, Berset, Catherine, Rondeau, Stephanie, Hawle, Hanne, Hitz, Felicitas, Pabst, Thomas, and Zander, Thilo
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- 2018
- Full Text
- View/download PDF
6. Consolidation Treatment with VRD Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant-Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Trial of the European Myeloma Network (EMN02/HO95)
- Author
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Sonneveld, Pieter, Beksac, Meral, Van Der Holt, Bronno, Dimopoulos, Meletios A, Carella, Angelo Michele, Ludwig, Heinz, Zweegman, Sonja, Zander, Thilo, Wester, Ruth, Hajek, Roman, Pantani, Lucia, Dozza, Luca, Gay, Francesca, Cafro, Anna Maria, De Rosa, Luca, Fioritoni, Francesca, Mellqvist, Ulf-Henrik, Troia, Rossella, Andersen, Niels Frost, Wu, Ka Lung, Driessen, Christoph, Carvalho, Susana, Croockewit, Alexandra J., Schjesvold, Fredrik, Offidani, Massimo, Cavo, Michele, and Boccadoro, Mario
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- 2020
- Full Text
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7. Human neutrophil peptides inhibit cleavage of von Willebrand factor by ADAMTS13: a potential link of inflammation to TTP
- Author
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Pillai, Vikram G., Bao, Jialing, Zander, Catherine B., McDaniel, Jenny K., Chetty, Palaniappan S., Seeholzer, Steven H., Bdeir, Khalil, Cines, Douglas B., and Zheng, X. Long
- Abstract
Infection or inflammation may precede and trigger formation of microvascular thrombosis in patients with acquired thrombotic thrombocytopenic purpura (TTP). However, the mechanism underlying this clinical observation is not fully understood. Here, we show that human neutrophil peptides (HNPs) released from activated and degranulated neutrophils inhibit proteolytic cleavage of von Willebrand factor (VWF) by ADAMTS13 in a concentration-dependent manner. Half-maximal inhibitory concentrations of native HNPs toward ADAMTS13-mediated proteolysis of peptidyl VWF73 and multimeric VWF are 3.5 μM and 45 μM, respectively. Inhibitory activity of HNPs depends on the RRY motif that is shared by the spacer domain of ADAMTS13. Native HNPs bind to VWF73 (KD = 0.72 μM), soluble VWF (KD = 0.58 μM), and ultra-large VWF on endothelial cells. Enzyme-linked immunosorbent assay (ELISA) demonstrates markedly increased plasma HNPs1-3 in most patients with acquired autoimmune TTP at presentation (median, ∼170 ng/mL; range, 58-3570; n = 19) compared with healthy controls (median, ∼23 ng/mL; range, 6-44; n = 18) (P < .0001). Liquid chromatography plus tandem mass spectrometry (LC-MS/MS) reveals statistically significant increases of HNP1, HNP2, and HNP3 in patient samples (all P values <.001). There is a good correlation between measurement of HNPs1-3 by ELISA and by LC-MS/MS (Spearman ρ = 0.7932, P < .0001). Together, these results demonstrate that HNPs1-3 may be potent inhibitors of ADAMTS13 activity, likely by binding to the central A2 domain of VWF and physically blocking ADAMTS13 binding. Our findings may provide a novel link between inflammation/infection and the onset of microvascular thrombosis in acquired TTP and potentially other immune thrombotic disorders.
- Published
- 2016
- Full Text
- View/download PDF
8. Human neutrophil peptides inhibit cleavage of von Willebrand factor by ADAMTS13: a potential link of inflammation to TTP
- Author
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Pillai, Vikram G., Bao, Jialing, Zander, Catherine B., McDaniel, Jenny K., Chetty, Palaniappan S., Seeholzer, Steven H., Bdeir, Khalil, Cines, Douglas B., and Zheng, X.Long
- Abstract
Infection or inflammation may precede and trigger formation of microvascular thrombosis in patients with acquired thrombotic thrombocytopenic purpura (TTP). However, the mechanism underlying this clinical observation is not fully understood. Here, we show that human neutrophil peptides (HNPs) released from activated and degranulated neutrophils inhibit proteolytic cleavage of von Willebrand factor (VWF) by ADAMTS13 in a concentration-dependent manner. Half-maximal inhibitory concentrations of native HNPs toward ADAMTS13-mediated proteolysis of peptidyl VWF73 and multimeric VWF are 3.5 μM and 45 μM, respectively. Inhibitory activity of HNPs depends on the RRY motif that is shared by the spacer domain of ADAMTS13. Native HNPs bind to VWF73 (KD= 0.72 μM), soluble VWF (KD= 0.58 μM), and ultra-large VWF on endothelial cells. Enzyme-linked immunosorbent assay (ELISA) demonstrates markedly increased plasma HNPs1-3 in most patients with acquired autoimmune TTP at presentation (median, ∼170 ng/mL; range, 58-3570; n = 19) compared with healthy controls (median, ∼23 ng/mL; range, 6-44; n = 18) (P< .0001). Liquid chromatography plus tandem mass spectrometry (LC-MS/MS) reveals statistically significant increases of HNP1, HNP2, and HNP3 in patient samples (all Pvalues <.001). There is a good correlation between measurement of HNPs1-3 by ELISA and by LC-MS/MS (Spearman ρ = 0.7932, P< .0001). Together, these results demonstrate that HNPs1-3 may be potent inhibitors of ADAMTS13 activity, likely by binding to the central A2 domain of VWF and physically blocking ADAMTS13 binding. Our findings may provide a novel link between inflammation/infection and the onset of microvascular thrombosis in acquired TTP and potentially other immune thrombotic disorders.
- Published
- 2016
- Full Text
- View/download PDF
9. Profile of Checkpoint Molecules Expression on Bone Marrow Cell Populations in Patients with High-Risk Myelodysplastic Syndrome
- Author
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Tcvetkov, Nikolai Yu., Morozova, Elena V., Epifanovskaya, Olga S., Babenko, Elena V., Barabanshikova, Maria V., Lepik, Kirill V., Bakin, Eugene A., Vlasova, Julia J., Smirnova, Anna G., Zander, Axel R., and Moiseev, Ivan S.
- Abstract
No relevant conflicts of interest to declare.
- Published
- 2020
- Full Text
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10. Factors Affecting Post-Transplant Relapse of Acute Lymphoblastic Leukemia (ALL) in Children According on the Intensity of Conditioning
- Author
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Semenova, Elena Vladimirovna, Kozhokar, Polina Valerievna, Paina, Olesia V, Rakhmanova, Zhemal Zarifovna, Frolova, Anastasia S, Tsvetkova, Luibov, Ekushov, Kirill Alexandrovich, Bykova, Tatiana A, Osipova, Anna A., Markova, Inna, Bondarenko, Sergey N., Smirnov, Boris I, Barkhatov, Ildar M, Gindina, Tatyana L., Moiseev, Ivan S., Zander, Axel R., and Zubarovskaya, Ludmila S
- Abstract
Background:
- Published
- 2020
- Full Text
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11. Predictive Model of Response to Blinatumomab Therapy in Children and Adults with Relapsed/Refractory B-ALL
- Author
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Markova, Inna, Bondarenko, Sergey N., Paina, Olesia V, Osipova, Anna A., Ayubova, Bella I, Bakin, Eugene A., Smirnova, Anna G., Babenko, Elena, Semenova, Elena Vladimirovna, Moiseev, Ivan S., Zander, Axel R., and Zubarovskaya, Ludmila S
- Abstract
No relevant conflicts of interest to declare.
- Published
- 2020
- Full Text
- View/download PDF
12. Upfront Autologous Hematopoietic Stem-Cell Transplantation Improves Overall Survival in Comparison with Bortezomib-Based Intensification Therapy in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the Randomized Phase 3 EMN02/HO95 Study
- Author
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Cavo, Michele, Gay, Francesca, Beksac, Meral, Dimopoulos, Meletios A, Pantani, Lucia, Petrucci, Maria Teresa, Dozza, Luca, Van Der Holt, Bronno, Zweegman, Sonja, Zamagni, Elena, Palumbo, Giuseppe A., Patriarca, Francesca, Galli, Monica, Maisnar, Vladimir, Hansson, Markus, Belotti, Angelo, Pour, Ludek, Ypma, Paula F, Grasso, Mariella, Croockewit, Sandra, Offidani, Massimo, Zambello, Renato, Liberati, Anna Marina, Andersen, Niels Frost, Broyl, Annemiek, Troia, Rossella, Musto, Pellegrino, Ludwig, Heinz, Morelli, Anna Maria, Hajek, Roman, Driessen, Christoph, Waage, Anders, Gimsing, Peter, Mellqvist, Ulf-Henrik, Zander, Thilo, Boccadoro, Mario, and Sonneveld, Pieter
- Abstract
Cavo: Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Gay:AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Petrucci:GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Maisnar:Janssen, Takeda, Amgen, BMS/Celgene, The Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Belotti:Celgene: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Liberati:Verastem: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Onconova: Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Ludwig:Seattle Genetics: Other: Advisory Boards; Takeda: Research Funding; Sanofi: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Celgene: Speakers Bureau. Hajek:Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.
- Published
- 2020
- Full Text
- View/download PDF
13. Upfront Autologous Hematopoietic Stem-Cell Transplantation Improves Overall Survival in Comparison with Bortezomib-Based Intensification Therapy in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the Randomized Phase 3 EMN02/HO95 Study
- Author
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Cavo, Michele, Gay, Francesca, Beksac, Meral, Dimopoulos, Meletios A, Pantani, Lucia, Petrucci, Maria Teresa, Dozza, Luca, Van Der Holt, Bronno, Zweegman, Sonja, Zamagni, Elena, Palumbo, Giuseppe A., Patriarca, Francesca, Galli, Monica, Maisnar, Vladimir, Hansson, Markus, Belotti, Angelo, Pour, Ludek, Ypma, Paula F, Grasso, Mariella, Croockewit, Sandra, Offidani, Massimo, Zambello, Renato, Liberati, Anna Marina, Andersen, Niels Frost, Broyl, Annemiek, Troia, Rossella, Musto, Pellegrino, Ludwig, Heinz, Morelli, Anna Maria, Hajek, Roman, Driessen, Christoph, Waage, Anders, Gimsing, Peter, Mellqvist, Ulf-Henrik, Zander, Thilo, Boccadoro, Mario, and Sonneveld, Pieter
- Abstract
Introduction:The multicentre, randomized, open-label, phase 3 EMN02/HO95 study for patients with newly diagnosed multiple myeloma (NDMM) included two randomization stages (1:1) to (R1) intensification therapy with either upfront ASCT or bortezomib-melphalan-prednisone (VMP), and thereafter to (R2) consolidation therapy or no consolidation, followed by lenalidomide maintenance in both arms. Results of the final analysis from R1 (M. Cavo et al. Lancet Haematol. 2020, 7, e456-68) showed that at a median follow-up of 60.5 months progression-free survival (PFS), the primary study endpoint, was significantly improved with ASCT compared with VMP (median, 57 versus 42 months; HR 0.73, 95% CI 0.62-0.85, adjusted p=0.0001). However, no difference between these groups was found in terms of overall survival (OS), a secondary endpoint (HR 0·90, 0·71-1·13, adjusted p=0·35).
- Published
- 2020
- Full Text
- View/download PDF
14. Predictive Model of Response to Blinatumomab Therapy in Children and Adults with Relapsed/Refractory B-ALL
- Author
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Markova, Inna, Bondarenko, Sergey N., Paina, Olesia V, Osipova, Anna A., Ayubova, Bella I, Bakin, Eugene A., Smirnova, Anna G., Babenko, Elena, Semenova, Elena Vladimirovna, Moiseev, Ivan S., Zander, Axel R., and Zubarovskaya, Ludmila S
- Abstract
Background.Blinatumomab is a monoclonal BITe antibody recently introduced for the treatment of relapsed and refractory (r\r) B-ALL. Response rate reaches 65-85% in different subgroups of patients but currently there is no reliable methods to predict response. Using results of the analysis of the efficacy of blinatumomab therapy in heterogenic cohort r/r B-ALL patients, including adults and children, we built a mathematical model to predict response to this antibody.
- Published
- 2020
- Full Text
- View/download PDF
15. High-Dose Chemotherapy with Bendamustin and Melphalan Improves the Rate of Complete Remission in Myeloma Patients in First Remission Compared to Standard Melphalan Alone
- Author
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Farag, Sarah, Bacher, Ulrike, Legros, Myriam, Betticher, Daniel, Lüthi, Jean-Marc, Egger, Thomas, Zander, Thilo, Jeker, Barbara, and Pabst, Thomas
- Abstract
Introduction:Consolidation of first-line induction treatment in myeloma (MM) patients (pts) with 200 mg/m2melphalan chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) was established as standard of care three decades ago. However, definite cure in myeloma patients remains exceptional due to residual disease escaping intensive treatment, and almost all patients will ultimately relapse at earlier or later time points following ASCT. Thus, improving efficacy of HDCT in MM remains an unresolved issue.
- Published
- 2020
- Full Text
- View/download PDF
16. The Outcome of Patients with Advanced Phase Chronic Myeloid Leukemia with and without Allogeneic Hemopoietic Stem Cell Transplantation
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Morozova, Elena V., Vlasova, Julia J., Barabanshikova, Maria V., Zander, Axel R., Jurovskaya, Ksenia, Gindina, Tatyana L., Barhatov, Ildar, Bondarenko, Sergey N., Moiseev, Ivan S., Zubarovskaya, Ludmila S, and Kulagin, Aleksandr D.
- Abstract
Introduction:
- Published
- 2020
- Full Text
- View/download PDF
17. Profile of Checkpoint Molecules Expression on Bone Marrow Cell Populations in Patients with High-Risk Myelodysplastic Syndrome
- Author
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Tcvetkov, Nikolai Yu., Morozova, Elena V., Epifanovskaya, Olga S., Babenko, Elena V., Barabanshikova, Maria V., Lepik, Kirill V., Bakin, Eugene A., Vlasova, Julia J., Smirnova, Anna G., Zander, Axel R., and Moiseev, Ivan S.
- Abstract
Background
- Published
- 2020
- Full Text
- View/download PDF
18. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti–T-cell globulin ATG-Fresenius
- Author
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Socié, Gérard, Schmoor, Claudia, Bethge, Wolfgang A., Ottinger, Hellmut D., Stelljes, Matthias, Zander, Axel R., Volin, Liisa, Ruutu, Tapani, Heim, Dominik A., Schwerdtfeger, Rainer, Kolbe, Karin, Mayer, Jiri, Maertens, Johan A., Linkesch, Werner, Holler, Ernst, Koza, Vladimir, Bornhäuser, Martin, Einsele, Hermann, Kolb, Hans-Jochem, Bertz, Hartmut, Egger, Matthias, Grishina, Olga, and Finke, Jürgen
- Abstract
Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P< .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P= .47, and HR = 0.68, P= .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P= .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P< .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.
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- 2011
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19. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti–T-cell globulin ATG-Fresenius
- Author
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Socié, Gérard, Schmoor, Claudia, Bethge, Wolfgang A., Ottinger, Hellmut D., Stelljes, Matthias, Zander, Axel R., Volin, Liisa, Ruutu, Tapani, Heim, Dominik A., Schwerdtfeger, Rainer, Kolbe, Karin, Mayer, Jiri, Maertens, Johan A., Linkesch, Werner, Holler, Ernst, Koza, Vladimir, Bornhäuser, Martin, Einsele, Hermann, Kolb, Hans-Jochem, Bertz, Hartmut, Egger, Matthias, Grishina, Olga, and Finke, Jürgen
- Abstract
Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.
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- 2011
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20. Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis
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Alchalby, Haefaa, Badbaran, Anita, Zabelina, Tatjana, Kobbe, Guido, Hahn, Joachim, Wolff, Daniel, Bornhäuser, Martin, Thiede, Christian, Baurmann, Herrad, Bethge, Wolfgang, Hildebrandt, York, Bacher, Ulrike, Fehse, Boris, Zander, Axel R., and Kröger, Nicolaus
- Abstract
Allogeneic stem cell transplantation (ASCT) after reduced-intensity conditioning has become a reasonable treatment option for patients with advanced myelofibrosis. The role of characteristic molecular genetic abnormalities, such as JAK2V617F on outcome of ASCT, is not yet elucidated. In 139 of 162 myelofibrosis patients with known JAK2V617F mutation status who received ASCT after reduced-intensity conditioning, the impact of JAK2 genotype, JAK2V617F allele burden, and clearance of mutation after ASCT was evaluated. Overall survival was significantly reduced in multivariate analysis in patients harboring JAK2 wild-type (hazard ratio = 2.14, P = .01) compared with JAK2 mutated patients. No significant influence on outcome was noted for the mutated allele burden analyzed either as continuous variable or after dividing into quartiles. Achievement of JAK2V617F negativity after ASCT was significantly associated with a decreased incidence of relapse (hazard ratio = 0.22, P = .04). In a landmark analysis, patients who cleared JAK2 mutation level in peripheral blood 6 months after ASCT had a significant lower risk of relapse (5% vs 35%, P = .03). We conclude that JAK2V617F-mutated status, but not allele frequency, resulted in an improved survival and rapid clearance after allografting reduces the risk of relapse.
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- 2010
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21. Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis
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Alchalby, Haefaa, Badbaran, Anita, Zabelina, Tatjana, Kobbe, Guido, Hahn, Joachim, Wolff, Daniel, Bornhäuser, Martin, Thiede, Christian, Baurmann, Herrad, Bethge, Wolfgang, Hildebrandt, York, Bacher, Ulrike, Fehse, Boris, Zander, Axel R., and Kröger, Nicolaus
- Abstract
Allogeneic stem cell transplantation (ASCT) after reduced-intensity conditioning has become a reasonable treatment option for patients with advanced myelofibrosis. The role of characteristic molecular genetic abnormalities, such as JAK2V617F on outcome of ASCT, is not yet elucidated. In 139 of 162 myelofibrosis patients with known JAK2V617F mutation status who received ASCT after reduced-intensity conditioning, the impact of JAK2 genotype, JAK2V617F allele burden, and clearance of mutation after ASCT was evaluated. Overall survival was significantly reduced in multivariate analysis in patients harboring JAK2 wild-type (hazard ratio = 2.14, P= .01) compared with JAK2 mutated patients. No significant influence on outcome was noted for the mutated allele burden analyzed either as continuous variable or after dividing into quartiles. Achievement of JAK2V617F negativity after ASCT was significantly associated with a decreased incidence of relapse (hazard ratio = 0.22, P= .04). In a landmark analysis, patients who cleared JAK2 mutation level in peripheral blood 6 months after ASCT had a significant lower risk of relapse (5% vs 35%, P= .03). We conclude that JAK2V617F-mutated status, but not allele frequency, resulted in an improved survival and rapid clearance after allografting reduces the risk of relapse.
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- 2010
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22. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV
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Saussele, Susanne, Lauseker, Michael, Gratwohl, Alois, Beelen, Dietrich W., Bunjes, Donald, Schwerdtfeger, Rainer, Kolb, Hans-Jochem, Ho, Anthony D., Falge, Christiane, Holler, Ernst, Schlimok, Günter, Zander, Axel R., Arnold, Renate, Kanz, Lothar, Dengler, Robert, Haferlach, Claudia, Schlegelberger, Brigitte, Pfirrmann, Markus, Müller, Martin C., Schnittger, Susanne, Leitner, Armin, Pletsch, Nadine, Hochhaus, Andreas, Hasford, Joerg, and Hehlmann, Rüdiger
- Abstract
The role of allogeneic stem cell transplantation in chronic myeloid leukemia is being reevaluated. Whereas drug treatment has been shown to be superior in first-line treatment, data on allogeneic hematopoietic stem cell transplantation (allo SCT) as second-line therapy after imatinib failure are scarce. Using an interim safety analysis of the randomized German CML Study IV designed to optimize imatinib therapy by combination, dose escalation, and transplantation, we here report on 84 patients who underwent consecutive transplantation according to predefined criteria (low European Group for Blood and Marrow Transplantation [EBMT] score, imatinib failure, and advanced disease). Three-year survival after transplantation of 56 patients in chronic phase was 91% (median follow-up: 30 months). Transplantation-related mortality was 8%. In a matched pair comparison of patients who received a transplant and those who did not, survival was not different. Three-year survival after transplantation of 28 patients in advanced phase was 59%. Eighty-eight percent of patients who received a transplant achieved complete molecular remissions. We conclude that allo SCT could become the preferred second-line option after imatinib failure for suitable patients with a donor. The study is registered at the National Institutes of Health, http://clinicaltrials.gov: NCT00055874.
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- 2010
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23. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV
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Saussele, Susanne, Lauseker, Michael, Gratwohl, Alois, Beelen, Dietrich W., Bunjes, Donald, Schwerdtfeger, Rainer, Kolb, Hans-Jochem, Ho, Anthony D., Falge, Christiane, Holler, Ernst, Schlimok, Günter, Zander, Axel R., Arnold, Renate, Kanz, Lothar, Dengler, Robert, Haferlach, Claudia, Schlegelberger, Brigitte, Pfirrmann, Markus, Müller, Martin C., Schnittger, Susanne, Leitner, Armin, Pletsch, Nadine, Hochhaus, Andreas, Hasford, Joerg, Hehlmann, Rüdiger, and Group, for the German CML Study
- Abstract
The role of allogeneic stem cell transplantation in chronic myeloid leukemia is being reevaluated. Whereas drug treatment has been shown to be superior in first-line treatment, data on allogeneic hematopoietic stem cell transplantation (allo SCT) as second-line therapy after imatinib failure are scarce. Using an interim safety analysis of the randomized German CML Study IV designed to optimize imatinib therapy by combination, dose escalation, and transplantation, we here report on 84 patients who underwent consecutive transplantation according to predefined criteria (low European Group for Blood and Marrow Transplantation [EBMT] score, imatinib failure, and advanced disease). Three-year survival after transplantation of 56 patients in chronic phase was 91% (median follow-up: 30 months). Transplantation-related mortality was 8%. In a matched pair comparison of patients who received a transplant and those who did not, survival was not different. Three-year survival after transplantation of 28 patients in advanced phase was 59%. Eighty-eight percent of patients who received a transplant achieved complete molecular remissions. We conclude that allo SCT could become the preferred second-line option after imatinib failure for suitable patients with a donor. The study is registered at the National Institutes of Health, http://clinicaltrials.gov: NCT00055874.
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- 2010
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24. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation
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Kröger, Nicolaus, Holler, Ernst, Kobbe, Guido, Bornhäuser, Martin, Schwerdtfeger, Rainer, Baurmann, Herrad, Nagler, Arnon, Bethge, Wolfgang, Stelljes, Matthias, Uharek, Lutz, Wandt, Hannes, Burchert, Andreas, Corradini, Paolo, Schubert, Jörg, Kaufmann, Martin, Dreger, Peter, Wulf, Gerald G., Einsele, Hermann, Zabelina, Tatjana, Kvasnicka, Hans Michael, Thiele, Jürgen, Brand, Ronald, Zander, Axel R., Niederwieser, Dietger, and de Witte, Theo M.
- Abstract
From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m2)–based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P = .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P = .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P = .02) and human leukocyte antigen–mismatched donor (hazard ratio = 3.04; P = .006) remained significant factors for survival. The study was registered at www.clinicaltrials.gov as #NCT 00599547.
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- 2009
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25. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation
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Kröger, Nicolaus, Holler, Ernst, Kobbe, Guido, Bornhäuser, Martin, Schwerdtfeger, Rainer, Baurmann, Herrad, Nagler, Arnon, Bethge, Wolfgang, Stelljes, Matthias, Uharek, Lutz, Wandt, Hannes, Burchert, Andreas, Corradini, Paolo, Schubert, Jörg, Kaufmann, Martin, Dreger, Peter, Wulf, Gerald G., Einsele, Hermann, Zabelina, Tatjana, Kvasnicka, Hans Michael, Thiele, Jürgen, Brand, Ronald, Zander, Axel R., Niederwieser, Dietger, and de Witte, Theo M.
- Abstract
From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m2)–based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P= .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P= .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P= .02) and human leukocyte antigen–mismatched donor (hazard ratio = 3.04; P= .006) remained significant factors for survival. The study was registered at www.clinicaltrials.govas #NCT 00599547.
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- 2009
- Full Text
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26. Comparison of and Immune Reconstitution and Graft Versus Host Disease in 30mg/Kg Anti-T-Lymphocyte Globuline with 60mg/Kg ATLG As Graft Versus Host Disease Prophylaxis in Matched Unrelated Donor Myeloablative Peripheral Blood Stem Cell Transplantation
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Massoud, Radwan, Klyuchnikov, Evgeny, Gagelmann, Nico, Zabelina, Tatjana, Christine, Wolschke, Ayuk, Francis Ayuketang, Fritsche-Friedland, Ulrike, Zander, Axel R., and Kröger, Nicolaus
- Abstract
Introduction:
- Published
- 2021
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27. Comparison of and Immune Reconstitution and Graft Versus Host Disease in 30mg/Kg Anti-T-Lymphocyte Globuline with 60mg/Kg ATLG As Graft Versus Host Disease Prophylaxis in Matched Unrelated Donor Myeloablative Peripheral Blood Stem Cell Transplantation
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Massoud, Radwan, Klyuchnikov, Evgeny, Gagelmann, Nico, Zabelina, Tatjana, Christine, Wolschke, Ayuk, Francis Ayuketang, Fritsche-Friedland, Ulrike, Zander, Axel R., and Kröger, Nicolaus
- Abstract
Ayuk: Celgene/BMS: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Miltenyi Biomedicine: Honoraria; Novartis: Honoraria; Takeda: Honoraria.
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- 2021
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28. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia
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Lee, Stephanie J., Kukreja, Manisha, Wang, Tao, Giralt, Sergio A., Szer, Jeffrey, Arora, Mukta, Woolfrey, Ann E., Cervantes, Francisco, Champlin, Richard E., Gale, Robert Peter, Halter, Joerg, Keating, Armand, Marks, David I., McCarthy, Philip L., Olavarria, Eduardo, Stadtmauer, Edward A., Abecasis, Manuel, Gupta, Vikas, Khoury, H. Jean, George, Biju, Hale, Gregory A., Liesveld, Jane L., Rizzieri, David A., Antin, Joseph H., Bolwell, Brian J., Carabasi, Matthew H., Copelan, Edward, Ilhan, Osman, Litzow, Mark R., Schouten, Harold C., Zander, Axel R., Horowitz, Mary M., and Maziarz, Richard T.
- Abstract
Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM+) and 900 subjects who did not receive IM before HCT (IM−) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM+ and IM− groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.
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- 2008
- Full Text
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29. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia
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Lee, Stephanie J., Kukreja, Manisha, Wang, Tao, Giralt, Sergio A., Szer, Jeffrey, Arora, Mukta, Woolfrey, Ann E., Cervantes, Francisco, Champlin, Richard E., Gale, Robert Peter, Halter, Joerg, Keating, Armand, Marks, David I., McCarthy, Philip L., Olavarria, Eduardo, Stadtmauer, Edward A., Abecasis, Manuel, Gupta, Vikas, Khoury, H. Jean, George, Biju, Hale, Gregory A., Liesveld, Jane L., Rizzieri, David A., Antin, Joseph H., Bolwell, Brian J., Carabasi, Matthew H., Copelan, Edward, Ilhan, Osman, Litzow, Mark R., Schouten, Harold C., Zander, Axel R., Horowitz, Mary M., and Maziarz, Richard T.
- Abstract
Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM+) and 900 subjects who did not receive IM before HCT (IM−) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM+and IM−groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.
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- 2008
- Full Text
- View/download PDF
30. RNA fingerprints provide direct evidence for the inhibitory role of TGFβ and PD-1 on CD4+ T cells in Hodgkin lymphoma
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Chemnitz, Jens M., Eggle, Daniela, Driesen, Julia, Classen, Sabine, Riley, James L., Debey-Pascher, Svenja, Beyer, Marc, Popov, Alexey, Zander, Thomas, and Schultze, Joachim L.
- Abstract
A hallmark of various human malignancies is the expression of immunoinhibitory factors within the tumor microenvironment. There is indirect evidence based on in vitro experiments that tumor-infiltrating T cells in human malignancies are suppressed by such factors. Still, direct evidence of the influence of individual inhibitory factors on immune cells in human cancer in vivo is lacking. To address this question, we used Hodgkin lymphoma (HL) as a model because histopathological characteristics of HL are thought to be due mostly to the effects of a wide variety of cytokines, including TGFβ or membrane-bound receptors such as PD-1 that are suspected to contribute to immune evasion of tumor cells. Using a genome-wide transcriptional approach, we established specific RNA fingerprints of TGFβ and PD-1 signaling in human T cells in vitro. Applying these specific fingerprints, we directly demonstrate that CD4+ T cells in HL—but not in follicular lymphoma (FL)—are under the inhibitory influence of both TGFβ and PD-1 in vivo. This approach can be easily generalized to provide direct evidence of the impact of any given soluble or cell-bound factor on any cell type within diseased tissue.
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- 2007
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31. RNA fingerprints provide direct evidence for the inhibitory role of TGFβ and PD-1 on CD4+T cells in Hodgkin lymphoma
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Chemnitz, Jens M., Eggle, Daniela, Driesen, Julia, Classen, Sabine, Riley, James L., Debey-Pascher, Svenja, Beyer, Marc, Popov, Alexey, Zander, Thomas, and Schultze, Joachim L.
- Abstract
A hallmark of various human malignancies is the expression of immunoinhibitory factors within the tumor microenvironment. There is indirect evidence based on in vitro experiments that tumor-infiltrating T cells in human malignancies are suppressed by such factors. Still, direct evidence of the influence of individual inhibitory factors on immune cells in human cancer in vivo is lacking. To address this question, we used Hodgkin lymphoma (HL) as a model because histopathological characteristics of HL are thought to be due mostly to the effects of a wide variety of cytokines, including TGFβ or membrane-bound receptors such as PD-1 that are suspected to contribute to immune evasion of tumor cells. Using a genome-wide transcriptional approach, we established specific RNA fingerprints of TGFβ and PD-1 signaling in human T cells in vitro. Applying these specific fingerprints, we directly demonstrate that CD4+T cells in HL—but not in follicular lymphoma (FL)—are under the inhibitory influence of both TGFβ and PD-1 in vivo. This approach can be easily generalized to provide direct evidence of the impact of any given soluble or cell-bound factor on any cell type within diseased tissue.
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- 2007
- Full Text
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32. Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
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Weissinger, Eva M., Schiffer, Eric, Hertenstein, Bernd, Ferrara, James L., Holler, Ernst, Stadler, Michael, Kolb, Hans-Jochem, Zander, Axel, Zürbig, Petra, Kellmann, Markus, and Ganser, Arnold
- Abstract
Acute graft-versus-host disease (aGvHD) contributes significantly to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of GvHD is mainly based on clinical features and tissue biopsies. A noninvasive, unbiased laboratory test for GvHD diagnosis does not exist. Here we describe the application of capillary electrophoresis coupled online with mass spectrometry (CE-MS) to 13 samples from 10 patients with aGvHD of grade II or more and 50 control samples from 23 patients without GvHD. About 170 GvHD-specific polypeptides were detected and a tentatively aGvHD-specific model consisting of 31 polypeptides was chosen, allowing correct classification of 13 of 13 (sensitivity 100.0% [95% confidence interval {CI} 75.1 to 100.0]) aGvHD samples and 49 of 50 (specificity 98.0% [95% CI 89.3 to 99.7]) control samples of the training set. The subsequent blinded evaluation of 599 samples enabled diagnosis of aGvHD greater than grade II, even prior to clinical diagnosis, with a sensitivity of 83.1% (95% CI 73.1 to 87.9) and a specificity of 75.6% (95% CI 71.6 to 79.4). Thus, high-resolution proteome analysis represents an unbiased laboratory-based screening method, enabling diagnosis, and possibly enabling preemptive therapy.
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- 2007
- Full Text
- View/download PDF
33. Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
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Weissinger, Eva M., Schiffer, Eric, Hertenstein, Bernd, Ferrara, James L., Holler, Ernst, Stadler, Michael, Kolb, Hans-Jochem, Zander, Axel, Zürbig, Petra, Kellmann, Markus, and Ganser, Arnold
- Abstract
Acute graft-versus-host disease (aGvHD) contributes significantly to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of GvHD is mainly based on clinical features and tissue biopsies. A noninvasive, unbiased laboratory test for GvHD diagnosis does not exist. Here we describe the application of capillary electrophoresis coupled online with mass spectrometry (CE-MS) to 13 samples from 10 patients with aGvHD of grade II or more and 50 control samples from 23 patients without GvHD. About 170 GvHD-specific polypeptides were detected and a tentatively aGvHD-specific model consisting of 31 polypeptides was chosen, allowing correct classification of 13 of 13 (sensitivity 100.0% [95% confidence interval {CI} 75.1 to 100.0]) aGvHD samples and 49 of 50 (specificity 98.0% [95% CI 89.3 to 99.7]) control samples of the training set. The subsequent blinded evaluation of 599 samples enabled diagnosis of aGvHD greater than grade II, even prior to clinical diagnosis, with a sensitivity of 83.1% (95% CI 73.1 to 87.9) and a specificity of 75.6% (95% CI 71.6 to 79.4). Thus, high-resolution proteome analysis represents an unbiased laboratory-based screening method, enabling diagnosis, and possibly enabling preemptive therapy.
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- 2007
- Full Text
- View/download PDF
34. Monitoring of the JAK2-V617F mutation by highly sensitive quantitative real-time PCR after allogeneic stem cell transplantation in patients with myelofibrosis
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Kröger, Nicolaus, Badbaran, Anita, Holler, Ernst, Hahn, Joachim, Kobbe, Guido, Bornhäuser, Martin, Reiter, Andreas, Zabelina, Tatjana, Zander, Axel R., and Fehse, Boris
- Abstract
The JAK2-V617F mutation occurs in about 50% of patients with myelofibrosis and might be a reliable marker to monitor residual disease after allogeneic stem cell transplantation. We describe a new, highly sensitive (≥ 0.01%) real-time polymerase chain reaction (PCR) to monitor and quantify V617F-JAK2–positive cells after dose-reduced allogeneic stem cell transplantation. After 22 allogeneic stem cell transplantation procedures in 21 JAK2-positive patients with myelofibrosis, 78% became PCR negative. In 15 of 17 patients (88%), JAK2 remained negative after a median follow-up of 20 months. JAK2 negativity was achieved after a median of 89 days after allograft (range, 19-750 days). A significant inverse correlation was seen for JAK2 positivity and donor-cell chimerism (r: −0.91, P < .001). Four of 5 patients who never achieved JAK2 negativity fulfilled during the entire follow-up all criteria for complete remission recently proposed by the International Working Group, suggesting a major role for JAK2 measurement to determine depths of remission. In one case, residual JAK2-positive cells were successfully eliminated by donor lymphocyte infusion. In conclusion, allogeneic stem cell transplantation after dose-reduced conditioning induces high rates of molecular remission in JAK2-positive patients with myelofibrosis, and quantification of V617F-JAK2 mutation by real-time PCR allows the detection of minimal residual disease to guide adoptive immunotherapy.
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- 2007
- Full Text
- View/download PDF
35. Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation
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Atanackovic, Djordje, Arfsten, Julia, Cao, Yanran, Gnjatic, Sacha, Schnieders, Frank, Bartels, Katrin, Schilling, Georgia, Faltz, Christiane, Wolschke, Christine, Dierlamm, Judith, Ritter, Gerd, Eiermann, Thomas, Hossfeld, Dieter Kurt, Zander, Axel R., Jungbluth, Achim A., Old, Lloyd J., Bokemeyer, Carsten, and Kröger, Nicolaus
- Abstract
Immunotherapies using cancer-testis (CT) antigens as targets represent a potentially useful treatment in patients with multiple myeloma (MM) who commonly show recurrent disease following chemotherapy. We analyzed the expression of 11 CT antigens in bone marrow samples from patients with MM (n = 55) and healthy donors (n = 32) using reverse transcriptase–polymerase chain reaction (RT-PCR). CT antigens were frequently expressed in MM with 56% (MAGEC2), 55% (MAGEA3), 35% (SSX1), 20% (SSX4, SSX5), 16% (SSX2), 15% (BAGE), 7% (NY-ESO-1), and 6% (ADAM2, LIPI) expressing the given antigen. Importantly, CT antigens were not expressed in healthy bone marrow. Analyzing patients with MM (n = 66) for antibody responses against MAGEA3, SSX2, and NY-ESO-1, we found strong antibody responses against CT antigens preferentially in patients who had received allogeneic stem cell transplantation (alloSCT). Antibody responses against NY-ESO-1 correlated with NY-ESO-1–specific CD4+ and CD8+ T-cell responses against peptide NY-ESO-151-62 and CD4+ responses against NY-ESO-1121-140 in 1 of these patients. These allogeneic immune responses were not detectable in pretransplantation samples and in the patients' stem cell donors, indicating that CT antigens might indeed represent natural targets for graft-versus-myeloma effects. Immune responses induced by alloSCT could be boosted by active CT antigen–specific immunotherapy, which might help to achieve long-lasting remissions in patients with MM.
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- 2007
- Full Text
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36. Monitoring of the JAK2-V617F mutation by highly sensitive quantitative real-time PCR after allogeneic stem cell transplantation in patients with myelofibrosis
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Kröger, Nicolaus, Badbaran, Anita, Holler, Ernst, Hahn, Joachim, Kobbe, Guido, Bornhäuser, Martin, Reiter, Andreas, Zabelina, Tatjana, Zander, Axel R., and Fehse, Boris
- Abstract
The JAK2-V617F mutation occurs in about 50% of patients with myelofibrosis and might be a reliable marker to monitor residual disease after allogeneic stem cell transplantation. We describe a new, highly sensitive (≥ 0.01%) real-time polymerase chain reaction (PCR) to monitor and quantify V617F-JAK2–positive cells after dose-reduced allogeneic stem cell transplantation. After 22 allogeneic stem cell transplantation procedures in 21 JAK2-positive patients with myelofibrosis, 78% became PCR negative. In 15 of 17 patients (88%), JAK2 remained negative after a median follow-up of 20 months. JAK2 negativity was achieved after a median of 89 days after allograft (range, 19-750 days). A significant inverse correlation was seen for JAK2 positivity and donor-cell chimerism (r: −0.91, P< .001). Four of 5 patients who never achieved JAK2 negativity fulfilled during the entire follow-up all criteria for complete remission recently proposed by the International Working Group, suggesting a major role for JAK2 measurement to determine depths of remission. In one case, residual JAK2-positive cells were successfully eliminated by donor lymphocyte infusion. In conclusion, allogeneic stem cell transplantation after dose-reduced conditioning induces high rates of molecular remission in JAK2-positive patients with myelofibrosis, and quantification of V617F-JAK2 mutation by real-time PCR allows the detection of minimal residual disease to guide adoptive immunotherapy.
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- 2007
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37. Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation
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Atanackovic, Djordje, Arfsten, Julia, Cao, Yanran, Gnjatic, Sacha, Schnieders, Frank, Bartels, Katrin, Schilling, Georgia, Faltz, Christiane, Wolschke, Christine, Dierlamm, Judith, Ritter, Gerd, Eiermann, Thomas, Hossfeld, Dieter Kurt, Zander, Axel R., Jungbluth, Achim A., Old, Lloyd J., Bokemeyer, Carsten, and Kröger, Nicolaus
- Abstract
Immunotherapies using cancer-testis (CT) antigens as targets represent a potentially useful treatment in patients with multiple myeloma (MM) who commonly show recurrent disease following chemotherapy. We analyzed the expression of 11 CT antigens in bone marrow samples from patients with MM (n = 55) and healthy donors (n = 32) using reverse transcriptase–polymerase chain reaction (RT-PCR). CT antigens were frequently expressed in MM with 56% (MAGEC2), 55% (MAGEA3), 35% (SSX1), 20% (SSX4, SSX5), 16% (SSX2), 15% (BAGE), 7% (NY-ESO-1), and 6% (ADAM2, LIPI) expressing the given antigen. Importantly, CT antigens were not expressed in healthy bone marrow. Analyzing patients with MM (n = 66) for antibody responses against MAGEA3, SSX2, and NY-ESO-1, we found strong antibody responses against CT antigens preferentially in patients who had received allogeneic stem cell transplantation (alloSCT). Antibody responses against NY-ESO-1 correlated with NY-ESO-1–specific CD4+and CD8+T-cell responses against peptide NY-ESO-151-62and CD4+responses against NY-ESO-1121-140in 1 of these patients. These allogeneic immune responses were not detectable in pretransplantation samples and in the patients' stem cell donors, indicating that CT antigens might indeed represent natural targets for graft-versus-myeloma effects. Immune responses induced by alloSCT could be boosted by active CT antigen–specific immunotherapy, which might help to achieve long-lasting remissions in patients with MM.
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- 2007
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38. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation
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Martino, Rodrigo, Parody, Rocio, Fukuda, Takahiro, Maertens, Johan, Theunissen, Koen, Ho, Aloysius, Mufti, Ghulam J., Kroger, Nicolaus, Zander, Arnold R., Heim, Dominik, Paluszewska, Monika, Selleslag, Dominik, Steinerova, Katerina, Ljungman, Per, Cesaro, Simone, Nihtinen, Anna, Cordonnier, Catherine, Vazquez, Lourdes, López-Duarte, Monica, Lopez, Javier, Cabrera, Rafael, Rovira, Montserrat, Neuburger, Stefan, Cornely, Oliver, Hunter, Ann E., Marr, Kieren A., Dornbusch, Hans Jürgen, and Einsele, Hermann
- Abstract
In this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillustherapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (≥ 3 risk factors, 72% incidence [P< .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT.
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- 2006
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39. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation
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Martino, Rodrigo, Parody, Rocio, Fukuda, Takahiro, Maertens, Johan, Theunissen, Koen, Ho, Aloysius, Mufti, Ghulam J., Kroger, Nicolaus, Zander, Arnold R., Heim, Dominik, Paluszewska, Monika, Selleslag, Dominik, Steinerova, Katerina, Ljungman, Per, Cesaro, Simone, Nihtinen, Anna, Cordonnier, Catherine, Vazquez, Lourdes, López-Duarte, Monica, Lopez, Javier, Cabrera, Rafael, Rovira, Montserrat, Neuburger, Stefan, Cornely, Oliver, Hunter, Ann E., Marr, Kieren A., Dornbusch, Hans Jürgen, and Einsele, Hermann
- Abstract
In this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillus therapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (≥ 3 risk factors, 72% incidence [P < .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT.
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- 2006
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40. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT
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Crawley, Charles, Szydlo, Richard, Lalancette, Marc, Bacigalupo, Andrea, Lange, Andrzej, Brune, Mats, Juliusson, Gunnar, Nagler, Arnon, Gratwohl, Alois, Passweg, Jakob, Komarnicki, Mieczysław, Vitek, Antonin, Mayer, Jiri, Zander, Axel, Sierra, Jorge, Rambaldi, Alessandro, Ringden, Olle, Niederwieser, Dietger, and Apperley, Jane F.
- Abstract
This study reports outcomes of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) in 186 patients with chronic myeloid leukemia (CML) from the European Group for Blood and Marrow Transplantation (EBMT). The median age was 50 years, and 64% were in first chronic phase (CP1), CP2 13%, accelerated phase 17%, and blast crises 6%. The median EBMT transplant score was 3. The day 100 transplantation-related mortality (TRM) was 6.1% (confidence interval [CI], 3.4%-11%) but rose to 23.3% (CI, 14%-27%) at 2 years. Fludarabine, busulfan, and antithymocyte globulin (Fd/Bu/ATG) was associated with the lowest TRM of 11.6% (CI, 4.7%-11%) at 1 year. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 32% and chronic GvHD in 43% (extensive in 24%). ATG was associated with a lower incidence of chronic GvHD (cGvHD). The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% (CI, 50%-66%) and 37% (CI, 30%-45%), respectively. Adverse OS was associated with advanced disease (relative risk [RR], 3.4). PFS was inferior in advanced disease (RR, 2.7) and a trend to improved outcomes with Fd/Bu/ATG (RR, 0.58). RIC allografts are feasible in CML in first or second CP. Since no other RIC regimen demonstrated superiority, Fd/Bu/ATG should be considered as baseline in future prospective trials.
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- 2005
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41. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT
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Crawley, Charles, Szydlo, Richard, Lalancette, Marc, Bacigalupo, Andrea, Lange, Andrzej, Brune, Mats, Juliusson, Gunnar, Nagler, Arnon, Gratwohl, Alois, Passweg, Jakob, Komarnicki, Mieczysław, Vitek, Antonin, Mayer, Jiri, Zander, Axel, Sierra, Jorge, Rambaldi, Alessandro, Ringden, Olle, Niederwieser, Dietger, and Apperley, Jane F.
- Abstract
This study reports outcomes of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) in 186 patients with chronic myeloid leukemia (CML) from the European Group for Blood and Marrow Transplantation (EBMT). The median age was 50 years, and 64% were in first chronic phase (CP1), CP2 13%, accelerated phase 17%, and blast crises 6%. The median EBMT transplant score was 3. The day 100 transplantation-related mortality (TRM) was 6.1% (confidence interval [CI], 3.4%-11%) but rose to 23.3% (CI, 14%-27%) at 2 years. Fludarabine, busulfan, and antithymocyte globulin (Fd/Bu/ATG) was associated with the lowest TRM of 11.6% (CI, 4.7%-11%) at 1 year. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 32% and chronic GvHD in 43% (extensive in 24%). ATG was associated with a lower incidence of chronic GvHD (cGvHD). The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% (CI, 50%-66%) and 37% (CI, 30%-45%), respectively. Adverse OS was associated with advanced disease (relative risk [RR], 3.4). PFS was inferior in advanced disease (RR, 2.7) and a trend to improved outcomes with Fd/Bu/ATG (RR, 0.58). RIC allografts are feasible in CML in first or second CP. Since no other RIC regimen demonstrated superiority, Fd/Bu/ATG should be considered as baseline in future prospective trials.
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- 2005
- Full Text
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42. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT
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Crawley, Charles, Lalancette, Marc, Szydlo, Richard, Gilleece, Maria, Peggs, Karl, Mackinnon, Stephen, Juliusson, Gunnar, Ahlberg, Lucia, Nagler, Arnon, Shimoni, Avichai, Sureda, Anna, Boiron, Jean-Michel, Einsele, Herman, Chopra, Rajesh, Carella, Angelo, Cavenagh, Jamie, Gratwohl, Alois, Garban, Frederic, Zander, Axel, Björkstrand, Bo, Niederwieser, Dietger, Gahrton, Gösta, and Apperley, Jane F.
- Abstract
We report the outcome of 229 patients who received an allograft for myeloma with reduced-intensity conditioning (RIC) regimens from 33 centers within the European Group for Blood and Marrow Transplantation (EBMT). The median age was 52 years and 64% were male. Conditioning regimens were heterogeneous, but most were fludarabine based and T cell depleted with antithymocyte globulin or alemtuzumab. Transplantation-related mortality (TRM) at 1 year was 22%. The 3-year overall survival (OS) and progression-free survival (PFS) were 41% and 21%, respectively. Adverse OS was associated with chemoresistant disease (relative risk [RR], 2.9), more than 1 prior transplantation (RR, 2.0), and male patients with female donors (RR, 1.45). Adverse PFS was associated with chemoresistance (RR, 2.4) and alemtuzumab (RR, 1.8). TRM was increased with female-to-male donation (RR, 2.5) and transplantation more than 1 year from diagnosis (RR, 2.3). Grades II to IV acute graft-versus-host disease (aGvHD) occurred in 31%. Chronic GvHD was associated with better OS and PFS and were 84% and 46% for limited, 58% and 30% for extensive, and 29% and 12% in its absence suggesting that a graft-versus-myeloma effect is important. While RIC is feasible, heavily pretreated patients and patients with progressive disease do not benefit.
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- 2005
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43. Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation
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Kröger, Nicolaus, Schilling, Georgia, Einsele, Hermann, Liebisch, Peter, Shimoni, Avichai, Nagler, Arnon, Perez-Simon, Jose A., San Miguel, Jesus F., Kiehl, Michael, Fauser, Axel, Schwerdtfeger, Rainer, Wandt, Hannes, Sayer, Herbert G., Myint, Han, Klingemann, Hans, Zabelina, Tatjana, Dierlamm, Judith, Hinke, Axel, and Zander, Axel R.
- Abstract
We investigated in a retrospective multicenter study the impact of chromosome arm 13q deletion (13q-) as detected by fluorescence in situ hybridization (FISH) on outcome after dose-reduced allografting in patients with multiple myeloma. In 68 of 140 patients, data on chromosome 13q status were available. Most patients included had advanced myeloma. At 2 years, patients with 13q deletion (n = 31) had a shorter event-free (18% vs 42%; P = .05) and overall survival (18% vs 67%; P = .03) than patients without 13q- (n = 37). Patients with 13q- experienced a higher relapse rate (77% vs 44%; P < .001) but a similar incidence of transplantation-related mortality at one year (24% vs 18%). In a multivariate analysis, 13q- remained a significant risk factor for a higher relapse rate (hazard ratio [HR], 3.28; 95% confidence interval [CI], 1.31-8.24; P = .01) and a shorter event-free survival (HR, 1.94; 95% CI, 1.03-3.67; P = .04). Concerning overall survival, 2 or more cycles of prior high-dose chemotherapy were associated with a significantly higher probability of death (HR, 2.48; 95% CI, 1.19-5.17; P = .02), while patients with deletion 13q had a nearly 2 times higher risk of death (HR, 1.94; 95% CI, 0.95-3.98; P = .07) after dose-reduced allogeneic stem cell transplantation.
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- 2004
- Full Text
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44. Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation
- Author
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Kröger, Nicolaus, Schilling, Georgia, Einsele, Hermann, Liebisch, Peter, Shimoni, Avichai, Nagler, Arnon, Perez-Simon, Jose A., San Miguel, Jesus F., Kiehl, Michael, Fauser, Axel, Schwerdtfeger, Rainer, Wandt, Hannes, Sayer, Herbert G., Myint, Han, Klingemann, Hans, Zabelina, Tatjana, Dierlamm, Judith, Hinke, Axel, and Zander, Axel R.
- Abstract
We investigated in a retrospective multicenter study the impact of chromosome arm 13q deletion (13q-) as detected by fluorescence in situ hybridization (FISH) on outcome after dose-reduced allografting in patients with multiple myeloma. In 68 of 140 patients, data on chromosome 13q status were available. Most patients included had advanced myeloma. At 2 years, patients with 13q deletion (n = 31) had a shorter event-free (18% vs 42%; P= .05) and overall survival (18% vs 67%; P= .03) than patients without 13q- (n = 37). Patients with 13q- experienced a higher relapse rate (77% vs 44%; P< .001) but a similar incidence of transplantation-related mortality at one year (24% vs 18%). In a multivariate analysis, 13q- remained a significant risk factor for a higher relapse rate (hazard ratio [HR], 3.28; 95% confidence interval [CI], 1.31-8.24; P= .01) and a shorter event-free survival (HR, 1.94; 95% CI, 1.03-3.67; P= .04). Concerning overall survival, 2 or more cycles of prior high-dose chemotherapy were associated with a significantly higher probability of death (HR, 2.48; 95% CI, 1.19-5.17; P= .02), while patients with deletion 13q had a nearly 2 times higher risk of death (HR, 1.94; 95% CI, 0.95-3.98; P= .07) after dose-reduced allogeneic stem cell transplantation.
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- 2004
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45. Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population
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Kustikova, Olga S., Wahlers, Anke, Kühlcke, Klaus, Stähle, Birgit, Zander, Axel R., Baum, Christopher, and Fehse, Boris
- Abstract
Retroviral vectors are commonly used in clinical gene therapy, but recent observations of insertional oncogene activation in preclinical and clinical settings have forced a discussion of their safety. Here we investigated the relationship between retroviral transduction efficiency in mass cultures and the actual number of integrated vector copies in single cells using K562 leukemia and primary CD34+ cells. We found an exponential increase of integration numbers correlated to gene transfer rates and a linear increase of expression levels with insertion frequency. On average we detected one vector insertion per transduced cell for a gene transfer of less than 30%, 3 for 60%, and approximately 9 for 90% (in K562). Clonal analysis revealed strikingly increased variations of both transgene copy numbers (more than 20-fold in primary cells) and expression levels associated with higher transduction. Therefore, limiting retroviral gene transfer to approximately 30% may be suggested to avoid generating clones containing multiple insertions.
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- 2003
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46. Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population
- Author
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Kustikova, Olga S., Wahlers, Anke, Kühlcke, Klaus, Stähle, Birgit, Zander, Axel R., Baum, Christopher, and Fehse, Boris
- Abstract
Retroviral vectors are commonly used in clinical gene therapy, but recent observations of insertional oncogene activation in preclinical and clinical settings have forced a discussion of their safety. Here we investigated the relationship between retroviral transduction efficiency in mass cultures and the actual number of integrated vector copies in single cells using K562 leukemia and primary CD34+cells. We found an exponential increase of integration numbers correlated to gene transfer rates and a linear increase of expression levels with insertion frequency. On average we detected one vector insertion per transduced cell for a gene transfer of less than 30%, 3 for 60%, and approximately 9 for 90% (in K562). Clonal analysis revealed strikingly increased variations of both transgene copy numbers (more than 20-fold in primary cells) and expression levels associated with higher transduction. Therefore, limiting retroviral gene transfer to approximately 30% may be suggested to avoid generating clones containing multiple insertions.
- Published
- 2003
- Full Text
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47. Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival
- Author
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Liu, Hongtao, Ma, Yingyu, Cole, Shawn M., Zander, Christopher, Chen, Kun-Hung, Karras, Jim, and Pope, Richard M.
- Abstract
The Bcl-2 family member Mcl-1 is essential for macrophage survival. However, the mechanisms that contribute to the expression of Mcl-1 in these cells have not been fully characterized. The present study focused on the role of signal transducer and activator of transcription 3 (STAT3) in regulation of Mcl-1 in macrophages. Sodium salicylate (NaSal) treatment induced apoptotic cell death in primary human macrophages in a dose- and time-dependent fashion. Incubation with NaSal resulted in the loss of mitochondrial transmembrane potential, the release of cytochromecand second mitochondria-derived activator of caspase/direct IAP binding protein with low pH of isoelectric point (pI) from the mitochondria, and the activation of caspases 9 and 3. Western blot analysis and reverse transcription—polymerase chain reaction demonstrated that NaSal down-regulated the expression of Mcl-1. Electrophoretic mobility shift assay and Western blot analysis for phosphorylated STAT3 demonstrated that STAT3 was constitutively activated in macrophages and that this STAT3 activation was suppressed by NaSal. The activation of STAT3 in macrophages was dependent on Ser727 phosphorylation, in the absence of detectable Tyr705phosphorylation. Ectopic expression of STAT3 in murine RAW264.7 macrophages rescued the inhibition of Mcl-1 promoter-reporter gene activation and the cell death induced by NaSal treatment, while a dominant-negative STAT3 resulted in cell death. To confirm its role in primary macrophages, STAT3 antisense (AS) oligodeoxynucleotides (ODNs) were employed. STAT3 AS, but not control, ODNs decreased STAT3 and Mcl-1 expression and resulted in macrophage apoptosis. These observations demonstrate that the STAT3-mediated expression of Mcl-1 is essential for the survival of primary human in vitro differentiated macrophages. (Blood. 2003;102:344-352)
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- 2003
- Full Text
- View/download PDF
48. Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival
- Author
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Liu, Hongtao, Ma, Yingyu, Cole, Shawn M., Zander, Christopher, Chen, Kun-Hung, Karras, Jim, and Pope, Richard M.
- Abstract
The Bcl-2 family member Mcl-1 is essential for macrophage survival. However, the mechanisms that contribute to the expression of Mcl-1 in these cells have not been fully characterized. The present study focused on the role of signal transducer and activator of transcription 3 (STAT3) in regulation of Mcl-1 in macrophages. Sodium salicylate (NaSal) treatment induced apoptotic cell death in primary human macrophages in a dose- and time-dependent fashion. Incubation with NaSal resulted in the loss of mitochondrial transmembrane potential, the release of cytochromecand second mitochondria-derived activator of caspase/direct IAP binding protein with low pH of isoelectric point (pI) from the mitochondria, and the activation of caspases 9 and 3. Western blot analysis and reverse transcription—polymerase chain reaction demonstrated that NaSal down-regulated the expression of Mcl-1. Electrophoretic mobility shift assay and Western blot analysis for phosphorylated STAT3 demonstrated that STAT3 was constitutively activated in macrophages and that this STAT3 activation was suppressed by NaSal. The activation of STAT3 in macrophages was dependent on Ser727phosphorylation, in the absence of detectable Tyr705phosphorylation. Ectopic expression of STAT3 in murine RAW264.7 macrophages rescued the inhibition of Mcl-1 promoter-reporter gene activation and the cell death induced by NaSal treatment, while a dominant-negative STAT3 resulted in cell death. To confirm its role in primary macrophages, STAT3 antisense (AS) oligodeoxynucleotides (ODNs) were employed. STAT3 AS, but not control, ODNs decreased STAT3 and Mcl-1 expression and resulted in macrophage apoptosis. These observations demonstrate that the STAT3-mediated expression of Mcl-1 is essential for the survival of primary human in vitro differentiated macrophages. (Blood. 2003;102:344-352)
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- 2003
- Full Text
- View/download PDF
49. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality
- Author
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Kröger, Nicolaus, Sayer, Herbert Gottfried, Schwerdtfeger, Rainer, Kiehl, Michael, Nagler, Arnon, Renges, Helmut, Zabelina, Tatjana, Fehse, Boris, Ayuk, Francis, Wittkowsky, Georg, Schmitz, Norbert, and Zander, Axel Rolf
- Abstract
We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m2), melphalan (100-140 mg/m2), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P= .04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.
- Published
- 2002
- Full Text
- View/download PDF
50. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality
- Author
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Kröger, Nicolaus, Sayer, Herbert Gottfried, Schwerdtfeger, Rainer, Kiehl, Michael, Nagler, Arnon, Renges, Helmut, Zabelina, Tatjana, Fehse, Boris, Ayuk, Francis, Wittkowsky, Georg, Schmitz, Norbert, and Zander, Axel Rolf
- Abstract
We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m2), melphalan (100-140 mg/m2), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P = .04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.
- Published
- 2002
- Full Text
- View/download PDF
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