21 results on '"Bjorn T. Gjertsen"'
Search Results
2. Prognostic Significance of Measurable Residual Disease Detection by Flow Cytometry in Autologous Stem Cell Apheresis Products in AML
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Jesse M. Tettero, Yara Buisman, Lok Lam Ngai, Costa Bachas, Bjorn T. Gjertsen, Angèle Kelder, Arjan A. van de Loosdrecht, Markus G. Manz, Thomas Pabst, Willemijn Scholten, Gert J. Ossenkoppele, Jacqueline Cloos, and David C. de Leeuw
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. Measurable residual disease-guided therapy in intermediate-risk acute myeloid leukemia patients is a valuable strategy in reducing allogeneic transplantation without negatively affecting survival
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Jesse M. Tettero, Lok Lam Ngai, Costa Bachas, Dimitri A. Breems, Thomas Fischer, Bjorn T. Gjertsen, Patrycja Gradowska, Laimonas Griskevicius, Jeroen J.W.M. Janssen, Gunnar Juliusson, Johan Maertens, Markus G. Manz, Thomas Pabst, Jakob Passweg, Kimmo Porkka, Peter J.M. Valk, Bob Löwenberg, Gert J. Ossenkoppele, and Jacqueline Cloos
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. The added value of multi‐state modelling in a randomized controlled trial: The HOVON 102 study re‐analyzed
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Katerina Bakunina, Hein Putter, Jurjen Versluis, Eva A. S. Koster, Bronno van derHolt, Markus G. Manz, Dimitri A. Breems, Bjorn T. Gjertsen, Jacqueline Cloos, Peter J. M. Valk, Jakob Passweg, Thomas Pabst, Gert J. Ossenkoppele, Bob Löwenberg, Jan J. Cornelissen, and Liesbeth C. deWreede
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AML ,clofarabine ,current leukemia‐free survival ,HSCT ,multi‐state model ,RCT ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi‐state models can provide additional insights to supplement the original intention‐to‐treat analysis of randomized controlled trials (RCT). We re‐analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi‐state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post‐remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post‐remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post‐remission treatment with alloSCT, non‐relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia‐free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi‐state models further detail the effect of treatment on competing and series of events.
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- 2022
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5. Concordance in measurable residual disease result after first and second induction cycle in acute myeloid leukemia: An outcome- and cost-analysis
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Jesse M. Tettero, Waleed K. W. Al-Badri, Lok Lam Ngai, Costa Bachas, Dimitri A. Breems, Catharina H. M. J. van Elssen, Thomas Fischer, Bjorn T. Gjertsen, Gwendolyn N. Y. van Gorkom, Patrycja Gradowska, Marjolein J. E. Greuter, Laimonas Griskevicius, Gunnar Juliusson, Johan Maertens, Markus G. Manz, Thomas Pabst, Jakob Passweg, Kimmo Porkka, Bob Löwenberg, Gert J. Ossenkoppele, Jeroen J. W. M. Janssen, and Jacqueline Cloos
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acute myeloid leukemia ,measurable residual disease (MRD) ,multiparameter flow cytometry (MFC) ,prognostic value ,earlier detection ,guided therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Measurable residual disease (MRD) measured using multiparameter flow-cytometry (MFC) has proven to be an important prognostic biomarker in acute myeloid leukemia (AML). In addition, MRD is increasingly used to guide consolidation treatment towards a non-allogenic stem cell transplantation treatment for MRD-negative patients in the ELN-2017 intermediate risk group. Currently, measurement of MFC-MRD in bone marrow is used for clinical decision making after 2 cycles of induction chemotherapy. However, measurement after 1 cycle has also been shown to have prognostic value, so the optimal time point remains a question of debate. We assessed the independent prognostic value of MRD results at either time point and concordance between these for 273 AML patients treated within and according to the HOVON-SAKK 92, 102, 103 and 132 trials. Cumulative incidence of relapse, event free survival and overall survival were significantly better for MRD-negative (
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- 2022
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6. Switching from imatinib to nilotinib plus pegylated interferon-α2b in chronic phase CML failing to achieve deep molecular response: clinical and immunological effects
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Inge G.P. Geelen, Stein-Erik Gullaksen, Mette M. Ilander, Ulla Olssen-Strömberg, Satu Mustjoki, Johan Richter, Nicole M.A. Blijlevens, Willem M. Smit, Bjorn T. Gjertsen, Tobias Gedde-Dahl, Berit Markevärn, Malika M.A. Koppes, Peter E. Westerweel, Henrik Hjorth-Hansen, Jeroen J.W.M. Janssen, Hematology, CCA - Cancer biology and immunology, and CCA - Imaging and biomarkers
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Hematology ,General Medicine ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response IS (MR 4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR 4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR 4.0 at month 12 (a BCR-ABL1 IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR 4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553.
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- 2023
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7. The <scp>NPM1</scp> mutant defines <scp>AML</scp> irrespective of blast count
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Brunangelo Falini, Maria Paola Martelli, Lorenzo Brunetti, Bjorn T. Gjertsen, and Vibeke Andresen
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Hematology - Published
- 2023
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8. Induction of a Systemic Immune Response during Use of an Allogenic Leukemia-Derived Dendritic Cell Vaccine in MRD+ AML Patients Correlates with Clinical Response and MRD Conversion
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Arjan A. Van de Loosdrecht, Jacqueline Cloos, Eva-Maria Wagner-Drouet, Uwe Platzbecker, Tobias A.W. Holderried, Catharina van Elssen, Aristoteles Giagounidis, Marij J.P. Welters, Sjoerd H. van der Burg, Hester J.T. van Zeeburg, Jeroen Rovers, and Bjorn T. Gjertsen
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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9. Use of an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in MRD+ AML-Patients Results in MRD Conversion, Improved Relapse-Free Survival and Vaccine Induced Immune Responses to Tumor Antigens
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Arjan A. Van de Loosdrecht, Jacqueline Cloos, Eva-Maria Wagner-Drouet, Uwe Platzbecker, Tobias A.W. Holderried, Catharina van Elssen, Aristoteles Giagounidis, Sören Lehmann, Hester J.T. van Zeeburg, Jeroen Rovers, and Bjorn T. Gjertsen
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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10. Overlapping features of therapy-related and de novoNPM1-mutated AML
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Jad Othman, Manja Meggendorfer, Enrico Tiacci, Christian Thiede, Richard Schlenk, Richard Dillon, Sebastian Stasik, Alessandra Venanzi, Sarah Bertoli, Eric Delabesse, Pierre-Yves Dumas, Arnaud Pigneux, Audrey Bidet, Amanda F. Gilkes, Ian Thomas, Maria Teresa Voso, Alessandro Rambaldi, Lorenzo Brunetti, Vincenzo M. Perriello, Vibeke Andresen, Bjorn T. Gjertsen, Maria Paola Martelli, Christian Récher, Christoph Röllig, Martin Bornhäuser, Hubert Serve, Carsten Müller-Tidow, Claudia D. Baldus, Tortsten Haferlach, Nigel Russell, and Brunangelo Falini
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Immunology ,Cell Biology ,Hematology ,Settore MED/15 ,Biochemistry - Abstract
NPM 1-mutated acute myeloid leukemia (AML) shows unique features. However, the characteristics of “therapy-related” NPM1-mutated AML (t-NPM1 AML) are poorly understood. We compared the genetics, transcriptional profile, and clinical outcomes of t-NPM1 AML, de novo NPM1-mutated AML (dn-NPM1 AML), and therapy-related AML (t-AML) with wild-type NPM1 (t-AML). Normal karyotype was more frequent in t-NPM1 AML (n = 78/96, 88%) and dn-NPM1 (n = 1986/2394, 88%) than in t-AML (n = 103/390, 28%; P < .001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n = 107), similar to dn-NPM1 (n = 88, 48% and 30%; P > 0.1), but more frequently than t-AML (n = 162; 14% and 10%; P < 0.001). Often mutated in t-AML, TP53 and PPM1D were wild-type in 97% and 96% of t-NPM1 AML, respectively. t-NPM1 and dn-NPM1 AML were transcriptionally similar, (including HOX genes upregulation). At 62 months of median follow-up, the 3-year overall survival (OS) for t-NPM1 AML (n = 96), dn-NPM1 AML (n = 2394), and t-AML (n = 390) were 54%, 60%, and 31%, respectively. In multivariable analysis, OS was similar for the NPM1-mutated groups (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.65-1.25; P = .45), but better in t-NPM1 AML than in t-AML (HR, 1.86; 95% CI, 1.30-2.68; P < .001). Relapse-free survival was similar between t-NPM1 and dn-NPM1 AML (HR, 1.02; 95% CI, 0.72-1.467; P = .90), but significantly higher in t-NPM1 AML versus t-AML (HR, 1.77; 95% CI, 1.19-2.64; P = .0045). t-NPM1 and dn-NPM1 AML have overlapping features, suggesting that they should be classified as a single disease entity.
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- 2022
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11. The added value of multi-state modelling in a randomized controlled trial
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Katerina Bakunina, Hein Putter, Jurjen Versluis, Eva A. S. Koster, Bronno Holt, Markus G. Manz, Dimitri A. Breems, Bjorn T. Gjertsen, Jacqueline Cloos, Peter J. M. Valk, Jakob Passweg, Thomas Pabst, Gert J. Ossenkoppele, Bob Löwenberg, Jan J. Cornelissen, Liesbeth C. Wreede, Hematology, Hematology laboratory, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, CCA - Cancer Treatment and quality of life, University of Zurich, and Bakunina, Katerina
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Cancer Research ,multi‐state model ,current leukemia‐free survival ,610 Medicine & health ,multi-state model ,SDG 3 - Good Health and Well-being ,AML ,Recurrence ,2741 Radiology, Nuclear Medicine and Imaging ,Humans ,Radiology, Nuclear Medicine and imaging ,1306 Cancer Research ,RC254-282 ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,current leukemia-free survival ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,clofarabine ,10032 Clinic for Oncology and Hematology ,HSCT ,2730 Oncology ,RCT - Abstract
Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events. publishedVersion
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- 2021
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12. Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis
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Monica Hellesøy, Caroline Engen, Tim Grob, Bob Löwenberg, Peter J. M. Valk, and Bjørn T. Gjertsen
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acute myeloid leukaemia ,context‐dependency ,FLT3 ,FLT3‐ITD ,sex disparity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex‐related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3‐ITD) mutation and co‐mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3‐ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML‐TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex‐associated molecular differences. Co‐occurrence of FLT3‐ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3‐ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia‐associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3‐ITD‐mutated AML. Thus, we suggest optimization of FLT3‐ITD mutation status as a clinical tool in a sex‐adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex‐specific considerations.
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- 2021
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13. FLT3‐ITD mutations in acute myeloid leukaemia – molecular characteristics, distribution and numerical variation
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Caroline Engen, Monica Hellesøy, Tim Grob, Adil Al Hinai, Atle Brendehaug, Line Wergeland, Siv Lise Bedringaas, Randi Hovland, Peter J. M. Valk, and Bjørn T. Gjertsen
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acute myeloid leukaemia ,FLT3‐ITD ,length mutation ,outcome ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Recurrent somatic internal tandem duplications (ITD) in the FMS‐like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3‐ITD mutation status guides risk‐adapted treatment strategies. The aim of this work was to characterise FLT3‐ITD variant distribution in relation to molecular and clinical features, and overall survival in adult AML patients. We performed two parallel retrospective cohort studies investigating FLT3‐ITD length and expression by cDNA fragment analysis, followed by Sanger sequencing in a subset of samples. In the two cohorts, a total of 139 and 172 mutant alleles were identified in 111 and 123 patients, respectively, with 22% and 28% of patients presenting with more than one mutated allele. Further, 15% and 32% of samples had a FLT3‐ITD total variant allele frequency (VAF)
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- 2021
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14. IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia
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Jani Huuhtanen, Mette Ilander, Bhagwan Yadav, Olli M.J. Dufva, Hanna Lähteenmäki, Tiina Kasanen, Jay Klievink, Ulla Olsson-Strömberg, Jesper Stentoft, Johan Richter, Perttu Koskenvesa, Martin Höglund, Stina Söderlund, Arta Dreimane, Kimmo Porkka, Tobias Gedde-Dahl, Björn T. Gjertsen, Leif Stenke, Kristina Myhr-Eriksson, Berit Markevärn, Anna Lübking, Andreja Dimitrijevic, Lene Udby, Ole Weis Bjerrum, Henrik Hjorth-Hansen, and Satu Mustjoki
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Hematology ,Immunology ,Medicine - Abstract
In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function.
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- 2022
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15. Contributors
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Michael J. Ackerman, Matthew L. Anderson, Felicita Andreotti, Brian H. Annex, Anthony Antonellis, Dmitri Artemov, James R. Bain, Peter J. Barnes, J.S. Barnholtz-Sloan, Richard C. Becker, Ivor J. Benjamin, Paul R. Billings, Simon C. Body, Mark Boguski, Stefano Bonassi, Brigitta Bondy, J. Martijn Bos, Roger E. Breitbart, Jerome Brody, Matthew P. Brown, Lars Bullinger, Shawn C. Burgess, Atul J. Butte, David J. Carey, George Carlson, Juan C. Celedón, Subhashini Chandrasekharan, Wing C. (John) Chang, Yan Chen, Antonio Chiocca, Theresa Puifun Chow, Wendy K. Chung, Robert Cook-Deegan, Dolores Corella, Susan Cottrell, Nancy J. Cox, Nigel P.S. Crawford, A. Jamie Cuticchia, Dieter Deforce, Mario C. Deng, Gayathri Devi, Theo deVos, Juergen Distler, Harmut Dohner, Ayotunde O. Dokun, Mark R. Edbrooke, Lucas B. Edelman, Dirk Elewaut, Charles J. Epstein, Ayman H. Fanous, Phillip G. Febbo, Robert J. Feezor, Yonmei Feng, Zeno Földes-Papp, Hidehiko Fujinaka, David J. Galas, Louis, P. Garrison, Glenn S. Gerhard, Geoffrey S. Ginsburg, Bjorn T. Gjertsen, Michael Glass, David B. Goldstein, Erynn S. Gordon, Tucker Gosnell, Peter Grass, Eric D. Green, Iris Grossman, Marta Gwinn, Carolina Haefliger, Susanne B. Haga, Per Hall, Joshua M. Hare, Ahmad Hariri, James R. Heath, Robert A. Hegele, Bettina Heidecker, Shona Hislop, Eric P. Hoffman, John Holton, Leroy Hood, Andrew T. Huang, Erich S. Huang, Carlos A. Hubbard, Kent Hunter, Courtney Hyland, Chunhwa Ihm, Olga Ilkayeva, Rafael Irizarry, Shushant Jain, Melissa D. Johnson, Philip W. Kantoff, Sekar Kathiresan, Hasmeena Kathuria, Kensaku Kawamoto, Filip De Keyser, Asif Khalid, Muin Khoury, Stephen F. Kingsmore, Michelle M. Kittleson, Beena T. Koshy, Ranga Krishnan, Robert S. Krouse, Vikas Kundra, Myla Lai-Goldman, Vipul Lakhani, Robert Langer, Sean E. Lawler, Inyoul Lee, Charles Lee, Arthur S. Lee, Stanely Leong, Ralf Lesche, Samuel Levy, Edison T. Liu, David F. Lobach, James B. Lorens, Aldons J. Lusis, H. Kim Lyerly, Nageswara R. Madamanchi, J. Alfredo Martinez, Vega Masignani, Kevin McGrath, John McHutchison, Frank Middleton, Herman Mielants, Michael J. Muehlbauer, Ulf Müller-Ladner, Mark A. Nelson, Monica Neri, Mihai Netea, L. Kristin Newby, Christopher B. Newgard, Maggie Ng, Paul W. Noble, Vasilis Ntziachristos, Robert L. Nussbaum, Meghan B. O'Donoghue, Kunle Odunsi, Kenneth Olden, Steve R. Ommen, Jose M. Ordovas, Roberto Patarca, Jeetendra Patel, K. Patel, Carlos N. Pato, Michele T. Pato, Tanja Pejovic, Noah C. Perin, Michael Pham, Robert M. Plenge, Achim Plum, Mihai V. Podgoreanu, Jonathan R. Pollack, Rebecca L. Pollex, Nathan D. Price, Thomas Quertermous, Francisco J. Quintana, Benjamin A. Raby, Daniel J. Rader, Sridhar Ramaswamy, Hans-Georg Rammensee, Scott D. Ramsey, Rino Rappuoli, Nader Rifai, Lisa Rimsza, Yu-Hui Rogers, Allen D. Roses, Jeffrey S. Ross, Ronenn Roubenoff, Marschall S. Runge, Maren T. Scheuner, Matthias Schuster, David A. Schwartz, Debra A. Schwinn, Chia Kee Seng, Nicholas A. Shackel, M. Frances Shannon, A. Dean Sherry, Jiaqi Shi, Kevin Shianna, Yelizaveta Shnayder, Andrew B. Singleton, T.P. Slavin, Desmond J. Smith, Rikkert L. Snoeckx, Ralph Snyderman, Avrum Spira, Colin F. Spraggs, Robert D. Stevens, Nicolas A. Stewart, Alison Stewart, F. Stewart, Robert L. Strausberg, Moshe Szyf, Weihong Tan, Robert I. Tepper, Hervé Tettelin, Giovana R. Thomas, John D. Thompson, Visith Thongboonkerd, Eric J. Topol, Jeffrey A. Towbin, Ad A. van Bodegraven, Kris Van Den Bogaert, Filip Van den Bosch, Matte Vatta, Timothy D. Veenstra, David L. Veenstra, Aleksandr E. Vendrov, Catherine M. Verfaillie, Nicole M. Walley, Ling Wang, Mike Weale, Michael E. Weinblatt, Howard L. Weiner, Scott T. Weiss, Ralph Weissleder, Samuel A. Wells, Brett R. Wenner, Ilse R. Wiechers, Georgia L. Wiesner, Janey L. Wiggs, Cisca Wijmenga, Huntington F. Willard, James M. Wilson, Nelson A. Wivel, Jay Wohlgemuth, Janet Woodcock, Christopher W. Woods, Paula W. Woon, Chana Yagil, Yoram Yagil, Tadashi Yamamoto, Gang Yao, Andrew J. Yee, Hyuntae Yoo, Y. Nancy You, Li-Rong Yu, Jean-François Zagury, Ron Zimmern, and Stephan Züchner
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- 2009
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16. Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial
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Robert J. Kreitman, Claire Dearden, Pier Luigi Zinzani, Julio Delgado, Tadeusz Robak, Philipp D. le Coutre, Bjørn T. Gjertsen, Xavier Troussard, Gail J. Roboz, Lionel Karlin, Douglas E. Gladstone, Nataliya Kuptsova-Clarkson, Shiyao Liu, Priti Patel, Federico Rotolo, Emmanuel Mitry, Ira Pastan, Francis Giles, and the Study 1053 investigators
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Hairy cell leukemia (HCL) ,B cell malignancy ,Relapsed/refractory ,CD22 ,Immunotoxin ,Moxetumomab pasudotox ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. Trial registration ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711
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- 2021
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17. Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types
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Muntasir M. Majumder, Aino-Maija Leppä, Monica Hellesøy, Paul Dowling, Alina Malyutina, Reidun Kopperud, Despina Bazou, Emma Andersson, Alun Parsons, Jing Tang, Olli Kallioniemi, Satu Mustjoki, Peter O’Gorman, Krister Wennerberg, Kimmo Porkka, Bjørn T. Gjertsen, and Caroline A. Heckman
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Innate drug sensitivity in healthy cells aids identification of lineage specific anti-cancer therapies and reveals off-target effects. To characterize the diversity in drug responses in the major hematopoietic cell types, we simultaneously assessed their sensitivity to 71 small molecules utilizing a multi-parametric flow cytometry assay and mapped their proteomic and basal signaling profiles. Unsupervised hierarchical clustering identified distinct drug responses in healthy cell subsets based on their cellular lineage. Compared to other cell types, CD19+/B and CD56+/NK cells were more sensitive to dexamethasone, venetoclax and midostaurin, while monocytes were more sensitive to trametinib. Venetoclax exhibited dose-dependent cell selectivity that inversely correlated to STAT3 phosphorylation. Lineage specific effect of midostaurin was similarly detected in CD19+/B cells from healthy, acute myeloid leukemia and chronic lymphocytic leukemia samples. Comparison of drug responses in healthy and neoplastic cells showed that healthy cell responses are predictive of the corresponding malignant cell response. Taken together, understanding drug sensitivity in the healthy cell-of-origin provides opportunities to obtain a new level of therapy precision and avoid off-target toxicity.
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- 2020
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18. CD24-targeted fluorescence imaging in patient-derived xenograft models of high-grade serous ovarian carcinoma
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Katrin Kleinmanns, Katharina Bischof, Shamundeeswari Anandan, Mihaela Popa, Lars A. Akslen, Vibeke Fosse, Ida Tveit Karlsen, Bjørn T. Gjertsen, Line Bjørge, and Emmet McCormack
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Optical imaging ,Fluorescence imaging ,HGSOC ,PDX ,Biomarker ,High-grade serous ovarian cancer ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: The survival rate of patients with advanced high-grade serous ovarian carcinoma (HGSOC) remains disappointing. Clinically translatable orthotopic cell line xenograft models and patient-derived xenografts (PDXs) may aid the implementation of more personalised treatment approaches. Although orthotopic PDX reflecting heterogeneous molecular subtypes are considered the most relevant preclinical models, their use in therapeutic development is limited by lack of appropriate imaging modalities. Methods: We developed novel orthotopic xenograft and PDX models for HGSOC, and applied a near-infrared fluorescently labelled monoclonal antibody targeting the cell surface antigen CD24 for non-invasive molecular imaging of epithelial ovarian cancer. CD24-Alexa Fluor 680 fluorescence imaging was compared to bioluminescence imaging in three orthotopic cell line xenograft models of ovarian cancer (OV-90luc+, Skov-3luc+ and Caov-3luc+, n = 3 per model). The application of fluorescence imaging to assess treatment efficacy was performed in carboplatin-paclitaxel treated orthotopic OV-90 xenografts (n = 10), before the probe was evaluated to detect disease progression in heterogenous PDX models (n = 7). Findings: Application of the near-infrared probe, CD24-AF680, enabled both spatio-temporal visualisation of tumour development, and longitudinal therapy monitoring of orthotopic xenografts. Notably, CD24-AF680 facilitated imaging of multiple PDX models representing different histological subtypes of the disease. Interpretation: The combined implementation of CD24-AF680 and orthotopic PDX models creates a state-of-the-art preclinical platform which will impact the identification and validation of new targeted therapies, fluorescence image-guided surgery, and ultimately the outcome for HGSOC patients. Funding: This study was supported by the H2020 program MSCA-ITN [675743], Helse Vest RHF, and Helse Bergen HF [911809, 911852, 912171, 240222, HV1269], as well as by The Norwegian Cancer Society [182735], and The Research Council of Norway through its Centers of excellence funding scheme [223250, 262652].
- Published
- 2020
- Full Text
- View/download PDF
19. Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia
- Author
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Heikki Kuusanmäki, Aino-Maija Leppä, Petri Pölönen, Mika Kontro, Olli Dufva, Debashish Deb, Bhagwan Yadav, Oscar Brück, Ashwini Kumar, Hele Everaus, Bjørn T. Gjertsen, Merja Heinäniemi, Kimmo Porkka, Satu Mustjoki, and Caroline A. Heckman
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
- Full Text
- View/download PDF
20. Early response evaluation in AML using mass cytometry
- Author
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Bjørn T. Gjertsen, Benedicte S. Tislevoll, Oda H.E. Fagerholt, and Monica Hellesøy
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
- Full Text
- View/download PDF
21. Drug Repurposing for the Treatment of Acute Myeloid Leukemia
- Author
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Vibeke Andresen and Bjørn T. Gjertsen
- Subjects
drug repurposing ,drug repositioning ,biomarkers ,cancer ,acute myeloid leukemia ,therapy development ,Medicine (General) ,R5-920 - Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of immature myeloid progenitor cells in the bone marrow, compromising of normal blood cell production and ultimately resulting in bone marrow failure. With a 20% overall survival rate at 5 years and 50% in the 18- to 65-year-old age group, new medicines are needed. It is proposed that development of repurposed drugs may be a part of the new therapy needed. AML is subdivided into recurrent molecular entities based on molecular genetics increasingly accessible for precision medicine. Novel therapy developments form a basis for novel multimodality therapy and include liposomal daunorubicin/cytarabine, broad or FLT3-specific tyrosine kinase inhibitors, Bcl-2 family inhibitors, selective inhibitors of nuclear export, metabolic inhibitors, and demethylating agents. The use of non-transplant immunotherapy is in early development in AML with the exceptional re-approval of a toxin-conjugated anti-CD33. However, the full potential of small molecule inhibitors and modalities like immunological checkpoint inhibitors, immunostimulatory small molecules, and CAR-T cell therapy is unknown. Some novel therapeutics will certainly benefit AML patient subgroups; however, due to high cost, more affordable alternatives are needed globally. Also the heterogeneity of AML will likely demand a broader repertoire of therapeutic molecules. Drug repurposing or repositioning represent a source for potential therapeutics with well-known toxicity profiles and reasonable prices. This implies that biomarkers of response need to accompany the development of antileukemic therapies for sharply defined patient subgroups. We will illustrate repurposing in AML with selected examples and discuss some experimental and regulatory limitations that may obstruct this development.
- Published
- 2017
- Full Text
- View/download PDF
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