35 results on '"Leo Ruhnke"'
Search Results
2. P556: A NEW MULTIPLEX PCR TOOL ENABLES TIMELY IDENTIFICATION OF ACTIONABLE TARGETS FOR MOLECULAR-GUIDED THERAPY IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
- Author
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Friedrich Stölzel, Leo Ruhnke, Heidi Altmann, Christoph Röllig, Martin Bornhauser, Triantafyllos Chavakis, Stephanie Nestler, Matthias Preussler, Anke Weber, and David Poitz
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. Midostaurin in addition to intensive chemotherapy in acute myeloid leukemia with t(8;21) and KIT and/or FLT3- ITD mutations: results of the SAL MIDOKIT trial
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Leo Ruhnke, Christoph Röllig, Sylvia Herold, Tim Sauer, Christian H. Brandts, Björn Steffen, Kerstin Schäfer-Eckart, Stefan W. Krause, Mathias Hänel, Albrecht Reichle, Sebastian Scholl, Andreas Neubauer, Jan-Henrik Mikesch, Johannes Schetelig, Friedrich Stölzel, Michael Kramer, Annett Haake, Julia Frimmel, Alwin Krämer, Richard Schlenk, Uwe Platzbecker, Hubert Serve, Claudia D. Baldus, Carsten Müller-Tidow, Daniela Aust, Martin Bornhäuser, Gerhard Ehninger, and Christian Thiede
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
- Full Text
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4. Biallelic TET2 mutations confer sensitivity to 5′-azacitidine in acute myeloid leukemia
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Friedrich Stölzel, Sarah E. Fordham, Devi Nandana, Wei-Yu Lin, Helen Blair, Claire Elstob, Hayden L. Bell, Brigitte Mohr, Leo Ruhnke, Desiree Kunadt, Claudia Dill, Daniel Allsop, Rachel Piddock, Emmanouela-Niki Soura, Catherine Park, Mohd Fadly, Thahira Rahman, Abrar Alharbi, Manja Wobus, Heidi Altmann, Christoph Röllig, Lisa Wagenführ, Gail L. Jones, Tobias Menne, Graham H. Jackson, Helen J. Marr, Jude Fitzgibbon, Kenan Onel, Manja Meggendorfer, Amber Robinson, Zuzanna Bziuk, Emily Bowes, Olaf Heidenreich, Torsten Haferlach, Sara Villar, Beñat Ariceta, Rosa Ayala Diaz, Steven J. Altschuler, Lani F. Wu, Felipe Prosper, Pau Montesinos, Joaquin Martinez-Lopez, Martin Bornhäuser, and James M. Allan
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Hematology ,Medicine - Abstract
Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5′-azacitidine (5′-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5′-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5′-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
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- 2023
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5. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia
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Wei-Yu Lin, Sarah E. Fordham, Eric Hungate, Nicola J. Sunter, Claire Elstob, Yaobo Xu, Catherine Park, Anne Quante, Konstantin Strauch, Christian Gieger, Andrew Skol, Thahira Rahman, Lara Sucheston-Campbell, Junke Wang, Theresa Hahn, Alyssa I. Clay-Gilmour, Gail L. Jones, Helen J. Marr, Graham H. Jackson, Tobias Menne, Mathew Collin, Adam Ivey, Robert K. Hills, Alan K. Burnett, Nigel H. Russell, Jude Fitzgibbon, Richard A. Larson, Michelle M. Le Beau, Wendy Stock, Olaf Heidenreich, Abrar Alharbi, David J. Allsup, Richard S. Houlston, Jean Norden, Anne M. Dickinson, Elisabeth Douglas, Clare Lendrem, Ann K. Daly, Louise Palm, Kim Piechocki, Sally Jeffries, Martin Bornhäuser, Christoph Röllig, Heidi Altmann, Leo Ruhnke, Desiree Kunadt, Lisa Wagenführ, Heather J. Cordell, Rebecca Darlay, Mette K. Andersen, Maria C. Fontana, Giovanni Martinelli, Giovani Marconi, Miguel A. Sanz, José Cervera, Inés Gómez-Seguí, Thomas Cluzeau, Chimène Moreilhon, Sophie Raynaud, Heinz Sill, Maria Teresa Voso, Francesco Lo-Coco, Hervé Dombret, Meyling Cheok, Claude Preudhomme, Rosemary E. Gale, David Linch, Julia Gaal-Wesinger, Andras Masszi, Daniel Nowak, Wolf-Karsten Hofmann, Amanda Gilkes, Kimmo Porkka, Jelena D. Milosevic Feenstra, Robert Kralovics, David Grimwade, Manja Meggendorfer, Torsten Haferlach, Szilvia Krizsán, Csaba Bödör, Friedrich Stölzel, Kenan Onel, and James M. Allan
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Science - Abstract
Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.
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- 2021
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6. Spatial heterogeneity and differential treatment response of acute myeloid leukemia and relapsed/refractory extramedullary disease after allogeneic hematopoietic cell transplantation
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Desiree Kunadt, Sylvia Herold, David Poitz, Lisa Wagenführ, Theresa Kretschmann, Katja Sockel, Leo Ruhnke, Stefan Brückner, Ulrich Sommer, Frieder Meier, Christoph Röllig, Malte von Bonin, Christian Thiede, Johannes Schetelig, Martin Bornhäuser, and Friedrich Stölzel
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Although extramedullary manifestations (EMs) are frequent in patients with acute myeloid leukemia (AML), they are often not detected during clinical workup and neither imaging- nor molecularly based diagnostic strategies are established to reveal their existence. Still, the detection of EM is essential for therapeutic decision-making, as EM present with aggressive and resistant disease and since mutational profiling might render patients within a different risk category, requiring personalized therapeutic strategies. Here, we report the case of an AML patient presenting with AML bone marrow (BM) infiltration and molecularly distinct EM at time of diagnosis followed by multiple EM relapses while undergoing several intensive chemotherapies including allogeneic hematopoietic cell transplantations (alloHCTs). 18 Fluorodesoxy-glucose positron emission tomography ( 18 FDG-PET)-imaging revealed EM sites in the mediastinum, duodenum, skin, and in retroperitoneal tissue, whereas recurrent BM biopsies showed continuous cytomorphologic and cytogenetic remission after alloHCT. To investigate the molecular background of the aggressive character of extramedullary disease and its differential treatment response, we performed amplicon-based next generation sequencing. An exon 4 (c.497_498insGA) frameshift RUNX1 mutation was exclusively found in all of the patient’s EM sites, but not in the BM or in peripheral blood samples at time of EM reoccurrence. In addition, we detected an exon 13 (c.3306G>T) ASXL1 point mutation only in the retroperitoneal tumor tissue at the time of the fourth relapse. In contrast to the patient’s intermediate-risk BM AML at diagnosis according to ELN2017, EM sites showed molecular adverse-risk features implicating intensified strategies like cellular therapies. Notably, disease relapse could only be detected by imaging throughout the course of disease. This case demonstrates both the necessity of continuous molecular profiling of EM to reveal differential molecular composition of EM and BM-derived AML, supposedly leading to divergent susceptibility to established therapies, as well as recurrent 18 FDG-PET-imaging for detecting residual disease and assessment of treatment response in case of EM AML.
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- 2022
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7. Long-Term Mixed Chimerism After Ex Vivo/In Vivo T Cell-Depleted Allogeneic Hematopoietic Cell Transplantation in Patients With Myeloid Neoplasms
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Leo Ruhnke, Friedrich Stölzel, Uta Oelschlägel, Malte von Bonin, Katja Sockel, Jan Moritz Middeke, Christoph Röllig, Korinna Jöhrens, Johannes Schetelig, Christian Thiede, and Martin Bornhäuser
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chimerism ,mixed donor chimerism ,allogeneic hematopoietic cell transplantation ,myeloid neoplasms ,AML ,CML ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In patients who have undergone allogeneic hematopoietic cell transplantation (HCT), myeloid mixed donor chimerism (MC) is a risk factor for disease relapse. In contrast, several studies found favorable outcome in patients with lymphoid MC. Thus far, most studies evaluating MC focused on a short-term follow-up period. Here, we report the first case series of long-term survivors with MC. We screened 1,346 patients having undergone HCT for myeloid neoplasms at our center from 1996 to 2016; 443 patients with data on total peripheral blood mononuclear cells (PBMC)/CD4+/CD34+ short tandem repeat (STR) donor chimerism (DC) and follow-up ≥24 months post-HCT were included. We identified 10 patients with long-term MC (PBMC DC
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- 2021
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8. Case Report: ANXA2 Associated Life-Threatening Coagulopathy With Hyperfibrinolysis in a Patient With Non-APL Acute Myeloid Leukemia
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Leo Ruhnke, Friedrich Stölzel, Lisa Wagenführ, Heidi Altmann, Uwe Platzbecker, Sylvia Herold, Andreas Rump, Evelin Schröck, Martin Bornhäuser, Johannes Schetelig, and Malte von Bonin
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acute promyelocytic leukemia ,acute myeloid leukemia ,hyperfibrinolysis ,disseminated intravascular coagulation ,coagulopathy ,ANXA2 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Patients with acute promyelocytic leukemia (APL) often present with potentially life-threatening hemorrhagic diathesis. The underlying pathomechanisms of APL-associated coagulopathy are complex. However, two pathways considered to be APL-specific had been identified: 1) annexin A2 (ANXA2)-associated hyperfibrinolysis and 2) podoplanin (PDPN)-mediated platelet activation and aggregation. In contrast, since disseminated intravascular coagulation (DIC) is far less frequent in patients with non-APL acute myeloid leukemia (AML), the pathophysiology of AML-associated hemorrhagic disorders is not well understood. Furthermore, the potential threat of coagulopathy in non-APL AML patients may be underestimated. Herein, we report a patient with non-APL AML presenting with severe coagulopathy with hyperfibrinolysis. Since his clinical course resembled a prototypical APL-associated hemorrhagic disorder, we hypothesized pathophysiological similarities. Performing multiparametric flow cytometry (MFC) and immunofluorescence imaging (IF) studies, we found the patient’s bone-marrow mononuclear cells (BM-MNC) to express ANXA2 - a biomarker previously thought to be APL-specific. In addition, whole-exome sequencing (WES) on sorted BM-MNC (leukemia-associated immunophenotype (LAIP)1: ANXAlo, LAIP2: ANXAhi) demonstrated high intra-tumor heterogeneity. Since ANXA2 regulation is not well understood, further research to determine the coagulopathy-initiating events in AML and APL is indicated. Moreover, ANXA2 and PDPN MFC assessment as a tool to determine the risk of life-threatening DIC in AML and APL patients should be evaluated.
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- 2021
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9. Author Correction: Genome-wide association study identifies susceptibility loci for acute myeloid leukemia
- Author
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Wei-Yu Lin, Sarah E. Fordham, Eric Hungate, Nicola J. Sunter, Claire Elstob, Yaobo Xu, Catherine Park, Anne Quante, Konstantin Strauch, Christian Gieger, Andrew Skol, Thahira Rahman, Lara Sucheston-Campbell, Junke Wang, Theresa Hahn, Alyssa I. Clay-Gilmour, Gail L. Jones, Helen J. Marr, Graham H. Jackson, Tobias Menne, Mathew Collin, Adam Ivey, Robert K. Hills, Alan K. Burnett, Nigel H. Russell, Jude Fitzgibbon, Richard A. Larson, Michelle M. Le Beau, Wendy Stock, Olaf Heidenreich, Abrar Alharbi, David J. Allsup, Richard S. Houlston, Jean Norden, Anne M. Dickinson, Elisabeth Douglas, Clare Lendrem, Ann K. Daly, Louise Palm, Kim Piechocki, Sally Jeffries, Martin Bornhäuser, Christoph Röllig, Heidi Altmann, Leo Ruhnke, Desiree Kunadt, Lisa Wagenführ, Heather J. Cordell, Rebecca Darlay, Mette K. Andersen, Maria C. Fontana, Giovanni Martinelli, Giovanni Marconi, Miguel A. Sanz, José Cervera, Inés Gómez-Seguí, Thomas Cluzeau, Chimène Moreilhon, Sophie Raynaud, Heinz Sill, Maria Teresa Voso, Francesco Lo-Coco, Hervé Dombret, Meyling Cheok, Claude Preudhomme, Rosemary E. Gale, David Linch, Julia Gaal-Wesinger, Andras Masszi, Daniel Nowak, Wolf-Karsten Hofmann, Amanda Gilkes, Kimmo Porkka, Jelena D. Milosevic Feenstra, Robert Kralovics, David Grimwade, Manja Meggendorfer, Torsten Haferlach, Szilvia Krizsán, Csaba Bödör, Friedrich Stölzel, Kenan Onel, and James M. Allan
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Science - Published
- 2022
- Full Text
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10. Progenitor Renin Lineage Cells are not involved in the regeneration of glomerular endothelial cells during experimental renal thrombotic microangiopathy.
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Leo Ruhnke, Jan Sradnick, Moath Al-Mekhlafi, Michael Gerlach, Florian Gembardt, Bernd Hohenstein, Vladimir T Todorov, and Christian Hugo
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Medicine ,Science - Abstract
Endothelial cells (EC) frequently undergo primary or secondary injury during kidney disease such as thrombotic microangiopathy or glomerulonephritis. Renin Lineage Cells (RLCs) serve as a progenitor cell niche after glomerular damage in the adult kidney. However, it is not clear whether RLCs also contribute to endothelial replenishment in the glomerulus following endothelial injury. Therefore, we investigated the role of RLCs as a potential progenitor niche for glomerular endothelial regeneration. We used an inducible tet-on triple-transgenic reporter strain mRen-rtTAm2/LC1/LacZ to pulse-label the renin-producing RLCs in adult mice. Unilateral kidney EC damage (EC model) was induced by renal artery perfusion with concanavalin/anti-concanavalin. In this model glomerular EC injury and depletion developed within 1 day while regeneration occurred after 7 days. LacZ-labelled RLCs were restricted to the juxtaglomerular compartment of the afferent arterioles at baseline conditions. In contrast, during the regenerative phase of the EC model (day 7) a subset of LacZ-tagged RLCs migrated to the glomerular tuft. Intraglomerular RLCs did not express renin anymore and did not stain for glomerular endothelial or podocyte cell markers, but for the mesangial cell markers α8-integrin and PDGFRβ. Accordingly, we found pronounced mesangial cell damage parallel to the endothelial injury induced by the EC model. These results demonstrated that in our EC model RLCs are not involved in endothelial regeneration. Rather, recruitment of RLCs seems to be specific for the repair of the concomitantly damaged mesangium.
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- 2018
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11. Neue Therapieoptionen bei der Akuten Myeloischen Leukämie
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Miriam Helena Eva Gediga, Jan Moritz Middeke, and Leo Ruhnke
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General Medicine - Published
- 2023
12. Next Generation Biobanking: Employing a Robotic System for Automated Mononuclear Cell Isolation
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Yannick F. Fuchs, Jonathan Brunner, Marc Weigelt, Anja Schieferdecker, Robert Morgenstern, Andrea Sturm, Boris Winter, Helena Jambor, Friedrich Stölzel, Leo Ruhnke, Malte von Bonin, Elke Rücker-Braun, Falk Heidenreich, Anke Fuchs, Ezio Bonifacio, Martin Bornhäuser, David M. Poitz, and Heidi Altmann
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Medicine (miscellaneous) ,Cell Biology ,General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
13. Supplementary Figures S1-S10 from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
- Abstract
This file contains supplementary figures S1-S10.
- Published
- 2023
14. Supplementary Tables S1-S7 from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
- Abstract
This excel file contains supplementary tables S1-S7.
- Published
- 2023
15. Supplementary Methods from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
- Author
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
- Abstract
This file contains supplementary methods and references.
- Published
- 2023
16. Data from Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
- Author
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Stefan Fröhling, Hanno Glimm, Wilko Weichert, Daniel Hübschmann, Evelin Schröck, Albrecht Stenzinger, Benedikt Brors, Barbara Klink, Christof von Kalle, Klaus Schulze-Osthoff, Michael Bitzer, Karsten Spiekermann, Philipp J. Jost, Nikolas von Bubnoff, Anna L. Illert, Melanie Boerries, Thomas Kindler, Christian H. Brandts, Jens Thomas Siveke, Sebastian Bauer, Gunnar Folprecht, Frederick Klauschen, Ulrich Keilholz, Richard F. Schlenk, Peter Schirmacher, Matthias Kroiss, Peter Hohenberger, Walter E. Aulitzky, Marinela Augustin, Ivo Buchhalter, Bettina Meißburger, Christina Geörg, Katrin Pfütze, Stephan Wolf, Ulrike Winter, Daniela Richter, Katja Beck, Roland Penzel, Olaf Neumann, Volker Endris, Andreas Laßmann, Leo Ruhnke, Michael Allgäuer, Daniel B. Lipka, Christoph E. Heilig, Veronica Teleanu, Dorothea Hanf, Lino Möhrmann, Laura Gieldon, Andreas Rump, Arne Jahn, Sebastian Uhrig, Martina Fröhlich, Jennifer Hüllein, Andreas Mock, Barbara Hutter, Simon Kreutzfeldt, Christoph Heining, and Peter Horak
- Abstract
The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population.Significance:Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659
- Published
- 2023
17. The diagnostic red blood cell distribution width as a prognostic factor in acute myeloid leukemia
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Katja Sockel, Georg-Nikolaus Franke, Vladan Vucinic, Leo Ruhnke, Madlen Jentzsch, Dietger Niederwieser, Dominic Brauer, Sebastian Schwind, Christoph Röllig, Martin Bornhäuser, Uwe Platzbecker, Maximilian Alexander Röhnert, and Donata Backhaus
- Subjects
Erythrocyte Indices ,Prognostic factor ,Erythrocytes ,business.industry ,Myeloid leukemia ,Red blood cell distribution width ,Hematology ,Prognosis ,Leukemia, Myeloid, Acute ,Cancer research ,Research Letter ,Medicine ,Humans ,business - Published
- 2021
18. Biallelic TET2 mutation sensitizes to 5'-azacitidine in acute myeloid leukemia
- Author
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Friedrich, Stölzel, Sarah E, Fordham, Devi, Nandana, Wei-Yu, Lin, Helen J, Blair, Claire J, Elstob, Hayden L, Bell, Brigitte, Mohr, Leo, Ruhnke, Desiree, Kunadt, Claudia, Dill, Daniel A, Allsop, Rachel E, Piddock, Emmanouela-Niki, Soura, Catherine Vida, Park, Mohd, Fadly, Thahira, Rahman, Abrar A, Alharbi, Manja, Wobus, Heidi, Altmann, Christoph, Röllig, Lisa, Wagenführ, Gail L, Jones, Tobias, Menne, Graham H, Jackson, Helen J, Marr, Jude, Fitzgibbon, Kenan, Onel, Manja, Meggendorfer, Amber, Robinson, Zuzanna, Bziuk, Emily, Bowes, Olaf, Heidenreich, Torsten, Haferlach, Sara, Villar, Beñat, Ariceta, Rosa, Ayala Diaz, Steven J, Altschuler, Lani, Wu, Felipe, Prosper, Pau, Montesinos, Joaquin, Martinez-Lopez, Martin, Bornhäuser, and James M, Allan
- Abstract
Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine (Ara-C), but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared to cells with monoallelic mutation. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.
- Published
- 2022
19. Venetoclax Plus High-Dose Cytarabine and Mitoxantrone As Feasible and Effective Novel Treatment for Relapsed AML: Results of the Phase-I SAL Relax Trial
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Christoph Röllig, Lars Fransecky, Maher Hanoun, Björn Steffen, Sabrina Kraus, Christoph Schliemann, Annett Haake, Frank Fiebig, Sven Zukunft, Nael Alakel, Jan Moritz Middeke, Martin Bornhaeuser, Friedrich Stoelzel, Johannes Schetelig, Leo Ruhnke, Michael Kramer, Malte Von Bonin, Maximilian Alexander Röhnert, Uta Oelschlägel, Claudia D. Baldus, Hubert Serve, and Martin Wermke
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
20. Prevalence, Clinical and Molecular Features, and Prognostic Value of Tetraploidy/Near-Tetraploidy in Patients with Acute Myeloid Leukemia
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Leo Ruhnke, Julia Frimmel, Christoph Röllig, Brigitte Mohr, Heidi Altmann, David Poitz, Sven Zukunft, Katrin Schranz, Sebastian Vosberg, Karsten Spiekermann, Michael von Bergwelt, Edgar Jost, Sabine Dressler, Kerstin Schäfer-Eckart, Triantafyllos Chavakis, Daniela Aust, Korinna Jöhrens, Gustavo Baretton, Martin Bornhäuser, Philipp A. Greif, Friedrich Stölzel, Sylvia Herold, and Lisa Wagenführ
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
21. Intensified cytarabine dose during consolidation in AML patients under 65 years is not associated with survival benefit: real-world data from the German SAL-AML registry
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Maher Hanoun, Leo Ruhnke, Michael Kramer, Christine Hanoun, Kerstin Schäfer-Eckart, Björn Steffen, Tim Sauer, Stefan Krause, Christoph Schliemann, Jan-Henrik Mikesch, Martin Kaufmann, Mathias Haenel, Edgar Jost, Tim Bruemmendorf, LArs Fransecky, Sabrina Kraus, Hermann Einsele, Dirk Niemann, Andreas Neubauer, Johannes Kullmer, Ruth Seggewiss-Bernhard, Martin Goerner, Gerhard Held, Ulrich Kaiser, Sebastian Scholl, Andreas Hochhaus, Hans Reinhardt, Uwe Platzbecker, Claudia Baldus, Carsten Müller-Tidow, Martin Bornhäuser, Hubert Serve, and Christoph Röllig
- Abstract
Higher doses of cytarabine appear to improve long-term outcome in acute myeloid leukemia (AML), in particular for younger patients. To this end, the optimal dosage of single agent cytarabine in consolidation therapy remains elusive. Here, we assessed the impact of different dosages of cytarabine consolidation after 7 + 3 induction on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Six-hundred-forty-two patients received HiDAC consolidation with median dosage of median 17.6 (IQR, 16.5–18.0) g/m² for a median number of 3 cycles (IQR, 2–3), whereas 178 patients received IDAC consolidation with 5.9 (IQR, 5.7–8.6) g/m² for a median of 2 cycles (IQR, 1–3). Both groups differed significantly in some important characteristics (age, sex, cytogenetic risk group, ECOG performance status, disease status, HCT-CI, number of induction cycles). After propensity score weighting for differences in patient and disease characteristics, relapse-free survival after 2 years was comparable between HiDAC-treated (55.3%) and IDAC-treated (55.6%) patients. Moreover, no significant differences in overall survival were observed after 2 years (84.7 vs. 80.6%). Notably, more patients treated with IDAC received allogeneic hematopoietic cell transplantation in first remission (37.6 vs. 19.8%, p
- Published
- 2022
22. Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse
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Andrew F. Berdel, Leo Ruhnke, Linus Angenendt, Martin Wermke, Christoph Röllig, Jan-Henrik Mikesch, Annika Scheller, Teresa Hemmerle, Mattia Matasci, Klaus Wethmar, Torsten Kessler, Mirjam Gerwing, Daniel Hescheler, Michael Schäfers, Wolfgang Hartmann, Bianca Altvater, Claudia Rossig, Martin Bornhäuser, Georg Lenz, Matthias Stelljes, Bjoern Rueter, Dario Neri, Wolfgang E. Berdel, and Christoph Schliemann
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Myeloid Neoplasia ,Immunobiology and Immunotherapy ,Clinical Trials and Observations ,Antibody-Dependent Cell Cytotoxicity ,Hematology ,Middle Aged ,Antibodies, Monoclonal, Humanized ,Immunoglobulin Fc Fragments ,Leukemia, Myeloid, Acute ,Recurrence ,Cytokines ,Humans ,Interleukin-2 - Abstract
Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK-cell–mediated antibody-dependent cellular cytotoxicity against leukemic blasts. In this novel-novel combination, dose-escalation, phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10 3 106 to 20 3 106 IU IV; days 1, 8, 15, and 22 of each 28-day cycle) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among the 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DLs), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills, and infusion-related reactions, which were manageable, transient and of grade #2. One dose-limiting toxicity occurred at each of DLs 3 (pulmonary edema) and 4 (graft-versus-host disease). Three objective responses were observed among 7 patients treated at the 2 higher DLs, whereas no responses occurred at the 2 starting DLs. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcgRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT as 2015-004763-37., Blood advances, 6 (12)
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- 2022
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23. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia
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Anne M. Dickinson, Gail Jones, David C. Linch, Clare Lendrem, David Grimwade, Richard A. Larson, Andrew D. Skol, Yaobo Xu, Adam Ivey, Wei-Yu Lin, Manja Meggendorfer, Rosemary E. Gale, Inés Gómez-Seguí, Giovani Marconi, Jean Norden, Jude Fitzgibbon, Mette K. Andersen, M Bornhäuser, Sarah E. Fordham, Amanda F. Gilkes, Heinz Sill, Eric A. Hungate, José Cervera, Friedrich Stölzel, Julia Gaal-Wesinger, Kim Piechocki, Wendy Stock, Theresa Hahn, Konstantin Strauch, David Allsup, Kenan Onel, Claire Elstob, Alyssa I. Clay-Gilmour, Nicola J. Sunter, Jelena D. Milosevic Feenstra, Meyling Cheok, Abrar Alharbi, Ann K. Daly, Sally Jeffries, Lisa Wagenführ, Olaf Heidenreich, Robert Kralovics, Alan K. Burnett, Giovanni Martinelli, Desiree Kunadt, Christian Gieger, Francesco Lo-Coco, Leo Ruhnke, Maria Teresa Voso, Junke Wang, Catherine Park, Nigel H. Russell, Chimène Moreilhon, Robert Kerrin Hills, Claude Preudhomme, Graham Jackson, Daniel Nowak, Maria Chiara Fontana, James M. Allan, Heidi Altmann, Richard S. Houlston, Anne S. Quante, Michelle M. Le Beau, Thahira Rahman, Christoph Röllig, Rebecca Darlay, Sophie Raynaud, Helen Marr, Csaba Bödör, Louise Palm, Thomas Cluzeau, Szilvia Krizsán, Heather J. Cordell, Mathew Collin, Torsten Haferlach, Lara E. Sucheston-Campbell, Wolf-Karsten Hofmann, Kimmo Porkka, Andras Masszi, Hervé Dombret, Miguel A. Sanz, Elisabeth Douglas, Tobias Menne, HUS Comprehensive Cancer Center, University Management, Helsinki University Hospital Area, Department of Oncology, and Hematologian yksikkö
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Oncology ,General Physics and Astronomy ,Genome-wide association study ,Disease ,0302 clinical medicine ,AML ,HLA Antigens ,hemic and lymphatic diseases ,Histone methylation ,Cancer genomics ,RISK ,0303 health sciences ,Multidisciplinary ,Myeloid leukemia ,Middle Aged ,CLONAL EVOLUTION ,CANCER ,3. Good health ,HLA ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,GENE-MUTATIONS ,medicine.medical_specialty ,Genotype ,Science ,Locus (genetics) ,HIF-1-ALPHA ,Human leukocyte antigen ,Polymorphism, Single Nucleotide ,Article ,Acute myeloid leukaemia ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Aldehyde Reductase ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,030304 developmental biology ,Genetic association ,OLDER PATIENTS ,Whites ,business.industry ,HUMAN-LEUKOCYTE ANTIGEN ,Reproducibility of Results ,Cancer ,General Chemistry ,Settore MED/15 ,medicine.disease ,IMMUNE ESCAPE ,Risk factors ,Case-Control Studies ,3111 Biomedicine ,business ,Genome-Wide Association Study - Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.
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- 2021
24. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia
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Michelle M. Le Beau, Thahira Rahman, Yaobo Xu, Wendy Stock, Andrew D. Skol, Abrar Alharbi, David Allsup, Claire Elstob, Lara E. Sucheston-Campbell, Lisa Wagenführ, Olaf Heidenreich, Claude Preudhomme, Tobias Menne, Szilvia Krizsán, Rebecca Darlay, Jelena D. Milosevic Feenstra, David C. Linch, Sophie Raynaud, Helen Marr, Christian Gieger, Francesco Lo-Coco, David Grimwade, Maria Teresa Voso, Junke Wang, Christoph Röllig, Clare Lendrem, Wolf-Karsten Hofmann, Mathew Collin, Manja Meggendorfer, Friedrich Stölzel, Wei-Yu Lin, Ann K. Daly, Theresa Hahn, Torsten Haferlach, Sally Jeffries, Julia Gaal-Wesinger, Konstantin Strauch, Giovani Marconi, Amanda F. Gilkes, Chimène Moreilhon, Giovanni Martinelli, Anne M. Dickinson, Robert Kerrin Hills, Alan K. Burnett, Mette K. Andersen, Leo Ruhnke, Kimmo Porkka, Catherine Park, Desiree Kunadt, Nigel H. Russell, M Bornhäuser, Alyssa I. Clay-Gilmour, Hervé Dombret, Sarah E. Fordham, Eric A. Hungate, Miguel A. Sanz, Inés Gómez-Seguí, Csaba Bödör, Jean Norden, Elisabeth Douglas, Rosemary E. Gale, Heinz Sill, Kim Piechocki, Richard A. Larson, Robert Kralovics, Meyling Cheok, Heidi Altmann, Richard S. Houlston, Andras Masszi, Anne S. Quante, Louise Palm, Thomas Cluzeau, Heather J. Cordell, Nicola J. Sunter, Graham Jackson, Daniel Nowak, Maria Chiara Fontana, James M. Allan, José Cervera, Kenan Onel, Gail Jones, Adam Ivey, and Jude Fitzgibbon
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0303 health sciences ,Myeloid leukemia ,Locus (genetics) ,Genome-wide association study ,Human leukocyte antigen ,Biology ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,030220 oncology & carcinogenesis ,Histone methylation ,Cancer research ,Etiology ,030304 developmental biology ,Genetic association - Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we performed a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identified a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identified a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N=1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology by identifying putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).
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- 2021
25. Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia
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Rachel Piddock, Claire Elstob, Abrar Alharbi, Emmanouela-Niki Soura, Graham Jackson, Joaquin Martinez-Lopez, Gail Jones, Tobias Menne, Brigitte Mohr, James M. Allan, Desiree Kunadt, Helen J. Blair, Jude Fitzgibbon, Christoph Röllig, Heidi Altmann, Claudia Dill, Leo Ruhnke, Manja Meggendorfer, Lisa Wagenführ, Olaf Heidenreich, Helen Marr, Sarah E. Fordham, Thahira Rahman, Kenan Onel, Mohd Fadly, Martin Bornhäuser, Torsten Haferlach, Friedrich Stölzel, Beñat Ariceta, Pau Montesinos, Wei-Yu Lin, Felipe Prosper, Catherine Park, Rosa Ayala Diaz, Devi Nandana, Daniel Allsop, Sara Villar, and Manja Wobus
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business.industry ,Point mutation ,Nonsense mutation ,Azacitidine ,Myeloid leukemia ,Cancer ,medicine.disease ,Leukemia ,Monoallelic Mutation ,Cancer research ,Cytarabine ,Medicine ,business ,medicine.drug - Abstract
Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutation (focal deletion and nonsense mutation) in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine, but acutely sensitive to 5’-azacitidine (5’-Aza) hypomethylating monotherapy, resulting in long-term morphological remission (overall survival (OS) 850 days). Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5’-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5’-Aza compared to cells with monoallelic mutation. We subsequently identified 29 additional patients from the Study Alliance Leukemia biobank with chromosome 4 abnormalities and identified two further patients with complex biallelic TET2 mutations, including one with trisomy 4, homozygosity across the long arm and an inactivating point mutation. We also screened patients recruited to the PETHEMA FLUGAZA phase 3 clinical trial and identified three patients with biallelic TET2 mutations, two of whom had responded very well to single agent 5’-Aza (OS 767 and 579 days) despite having adverse risk AML and poor performance status. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.Key PointsMutant TET2 allele dosage affects response to 5’-azacitidine in acute myeloid leukemia in vitro and in a xenograft model.Our data highlight the importance for screening of biallelic mutations to predict response to therapy in acute myeloid leukemia.
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- 2021
26. Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR T-cell treatment
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Raphael Teipel, Frank Kroschinsky, Michael Kramer, Theresa Kretschmann, Katharina Egger-Heidrich, Thomas Krüger, Leo Ruhnke, Sylvia Herold, Sebastian Stasik, Katja Sockel, Jan M. Middeke, Karolin Trautmann-Grill, Martin Bornhäuser, Christian Thiede, and Malte von Bonin
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Lymphoma, B-Cell ,Receptors, Chimeric Antigen ,Lymphoma, Non-Hodgkin ,T-Lymphocytes ,Antigens, CD19 ,Prevalence ,Humans ,Neurotoxicity Syndromes ,Hematology ,Clonal Hematopoiesis ,Cytokine Release Syndrome - Abstract
Inflammation plays an important role in chimeric antigen receptor (CAR) T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR T-cell treatment is widely unknown. We evaluated the prevalence of CHIP, using a targeted deep sequencing approach, in a cohort of patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma before and after CAR T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia, and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34%) before CAR T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR T-cell treatment but had an improved overall survival (not reached vs 265 days, P = .003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic use of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (with the exception of ferritin), or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR T-cell therapy and is not associated with an inferior outcome.
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- 2021
27. Abstract CT188: ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial
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Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, and Paul Frohna
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Cancer Research ,Oncology - Abstract
Background: γ9δ2 T cells are part of the innate-like immune response to malignancies and have the ability to bridge to the adaptive immune response via cytokine release (e.g., IFNγ and TNFα). Butyrophilin 3A is a novel checkpoint molecule required to activate γ9δ2 T cells highly expressed on immune and malignant cells, and the target of a monoclonal antibody ICT01. ICT01 induces activation/migration of γ9δ2 T cells from the blood to induce immune remodeling of the tumor microenvironment at doses ≥700 μg being tested in the ongoing EVICTION clinical trial (NCT04243499) (AACR 2021, CT034). In vitro studies showed that ICT01 induces upregulation of PD-1 on γ9δ2 T cells and that the combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale for evaluating this combination. Methods: EVICTION is an ongoing Phase 1/2a, international, open-label trial with Group C assessing ICT01 (IV Q3W) plus pembrolizumab (200mg IV Q3W) in patients with bladder cancer, HNSCC, melanoma, or NSCLC who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations by i/RECIST 1.1 were conducted every 8 weeks. Results: Five Group C patient cohorts have been enrolled and treated with ICT01 doses of 700μg, 2mg, 7mg, 20mg or 75mg (n=30) plus pembrolizumab, with the 200mg ICT01 cohort enrolling currently. To date, no DLTs have been observed with the combination. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency up to 75mg (100%, n=6), without any increase in severity, and rarely recur with subsequent dosing. ICT01+pembrolizumab induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥700 μg), which was sustained for 21 days at 75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and returned to baseline by 24 hrs post dose. Baseline γ9δ2 T cell count also correlated with increases in tumor infiltration of γδ, CD3, and CD8 T cells, confirming the ability to remodel the TME, and the potential to select/enrich patients with higher baseline γ9δ2 T cell counts. Sixteen patients (9/16 pembro-experienced, 5/16 received >1 prior CPI) were efficacy-evaluable at ≥Week 8 by RECIST1.1 at ICT01 doses up to 20 mg, with an observed disease control rate of 44% including 3 confirmed PRs beyond 6 months: bladder (2mg), melanoma (2mg), NSCLC (7mg). The Ipi/Nivo-refractory melanoma patient with PR also achieving a CR on their non-target lesion brain metastasis at 6 months. Data from the 75 and 200mg cohorts will be presented. Conclusion: The immune remodeling of the TME by ICT01-activated γ9δ2 T cells is associated with clinical benefit in CPI-experienced patients when used in combination with pembrolizumab. The selection of patients with higher baseline γ9δ2 T cells may improve the response profile to this novel therapeutic combination in CPI-failure patients, which will be tested in the Phase 2a portion of EVICTION starting in Q2 2022. Citation Format: Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, Paul Frohna. ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT188.
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- 2022
28. Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
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Stefan Fröhling, Albrecht Stenzinger, Ivo Buchhalter, Peter Hohenberger, Sebastian Bauer, Ulrich Keilholz, Andreas Mock, Daniel B. Lipka, Benedikt Brors, Michael Allgäuer, Andreas Rump, Stephan Wolf, Melanie Boerries, Klaus Schulze-Osthoff, Gunnar Folprecht, Katrin Pfütze, Christof von Kalle, Christian Brandts, Michael Bitzer, Laura Gieldon, Arne Jahn, Peter Schirmacher, Olaf Neumann, Matthias Kroiss, Barbara Klink, Daniela Richter, Sebastian Uhrig, Peter Horak, Ulrike Winter, Nikolas von Bubnoff, Barbara Hutter, Walter E. Aulitzky, Wilko Weichert, Jennifer Hüllein, Philipp J. Jost, Veronica Teleanu, Thomas Kindler, Leo Ruhnke, Martina Fröhlich, Christoph E. Heilig, Katja Beck, Karsten Spiekermann, Volker Endris, Evelin Schröck, Frederick Klauschen, Dorothea Hanf, Simon Kreutzfeldt, Daniel Hübschmann, Jens T. Siveke, Bettina Meißburger, Lino Möhrmann, Richard F. Schlenk, Andreas Laßmann, Anna Lena Illert, Roland Penzel, Christina Geörg, Christoph Heining, Marinela Augustin, and Hanno Glimm
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Oncology ,medicine.medical_specialty ,business.industry ,Genetic counseling ,MEDLINE ,Medizin ,Cancer ,medicine.disease ,Clinical trial ,Transcriptome ,Internal medicine ,Medicine ,Clinical significance ,Observational study ,business ,Exome - Abstract
The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. Significance: Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677. This article is highlighted in the In This Issue feature, p. 2659
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- 2021
29. A Phase I Trial of the Antibody-Cytokine Fusion Protein F16IL2 in Combination with Anti-CD33 Immunotherapy for Posttransplant AML Relapse
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Christoph Schliemann, Georg Lenz, Matthias Stelljes, Claudia Rossig, Mirjam Gerwing, Wolfgang E. Berdel, Torsten Kessler, Leo Ruhnke, Daniel Hescheler, Jan-Henrik Mikesch, Martin Wermke, Andrew F. Berdel, Bianca Altvater, Wolfgang Hartmann, Klaus Wethmar, Christoph Röllig, Bjoern Rueter, Dario Neri, Linus Angenendt, Teresa Hemmerle, and Michael Schäfers
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biology ,business.industry ,medicine.medical_treatment ,Immunology ,CD33 ,Cell Biology ,Hematology ,Immunotherapy ,Biochemistry ,Fusion protein ,Cytokine ,Phase (matter) ,Cancer research ,medicine ,biology.protein ,Antibody ,business - Abstract
Introduction Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but shortage of environmental growth factors and deficient recognition of malignant cells may limit their anticancer efficacy. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to the leukemia-modified extracellular matrix (ECM) would increase NK cell abundance and activity to potentiate antibody-dependent cellular cytotoxicity (ADCC) against acute myeloid leukemia (AML) blasts. In this novel-novel combination dose-escalation phase 1 trial, we enrolled patients with AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of F16IL2, an antibody-cytokine fusion protein composed of the human antibody fragment scFv(F16) in diabody format and two molecules of human IL-2, in combination with the Fc-optimized, ADCC-mediating anti-CD33 monoclonal antibody BI 836858. F16 specifically targets the A1 domain of the ECM protein tenascin C (TnC), which is spliced into the TnC molecule during active angiogenesis and tissue remodeling while it is virtually absent in normal tissues. Methods F16IL2 (10 - 20 Mio IU IV) was administered on days 1, 8, 15 and 22 of 28-day cycles, followed by administration of BI 836858 (10 - 40 mg IV) two days after each F16IL2 infusion. Dose escalation was performed over 4 dose levels (DL). Cohort 1 (10 Mio IU F16IL2 and 10 mg BI 836858, n = 5), cohort 2 (10 Mio IU F16IL2 and 20 mg BI 836858, n = 3), cohort 3 (20 Mio IU F16IL2 and 20 mg BI 836858, n = 4), cohort 4 (20 Mio IU F16IL2 and 40 mg BI 836858, n = 3). Safety and tolerability, pharmacodynamics and -kinetics, clinical efficacy and immune effector cell dynamics were investigated. This trial was registered at EudraCT as #2015-004763-37. Results Between December 2016 and March 2020, 15 patients with a median age of 50 years (range, 20 - 68) were enrolled and treated across 4 dose levels. Six patients (40%) had received two or more prior HSCT. The most frequent drug-related AEs (F16IL2 or BI 836858 or combination) were pyrexia (n = 13, 87%), chills (n = 12, 80%) and infusion-related reactions (n = 9, 60%), consistent with the expected toxicity profile of cytokine-armed or naked mAbs. These events were generally manageable, transient and of grade ≤ 2. One dose-limiting toxicity occurred at each of DL 3 (pulmonary edema) and 4 (acute GVHD). No patient died within the first 30 days of treatment initiation. Whereas no formal maximum tolerated dose (MTD) was reached, the maximum tested dose of 20 Mio IU F16IL2 and 40 mg BI 836858 was considered the recommended dose (RD). Three objective responses (1 CR, 1 CRi, 1 PR in extramedullary AML) were observed among 7 patients treated at the two higher DL, whereas no responses occurred at the two starting DL. Median OS among all 15 patients was 4.8 months (1.5 - 12.9), with a 6- and 12-month OS of 40% and 27%, respectively. Among those 7 patients whose AML was at least temporarily controlled with study treatment (CR/CRi, PR, SD), 12-month OS was 67% vs. 0% in non-responders. Combination therapy stimulated the expansion and activation of NK cells in bone marrow and peripheral blood. Conclusions To the best of our knowledge, this is the first study demonstrating that the strategy of potentiating ADCC with tumor-targeted immunocytokines is feasible in humans. In the difficult-to-treat situation of posttransplant AML relapse, responses were observed at higher DL, even in patients with extramedullary disease. The antibody-mediated targeted delivery of IL-2 to the ECM combined with anti-CD33 immunotherapy represents an innovative experimental approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. Disclosures Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Hemmerle: Philogen S.p.A.: Current Employment. Schäfers: Philogen S.p.A.: Research Funding. Rossig: BMS and Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; AdBoards by Amgen: Honoraria. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Rueter: Boehringer Ingelheim Pharma GmbH & Co. KG: Current Employment. Neri: Philogen S.p.A.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Multiple patents on vascular targeting; ETH Zurich: Patents & Royalties: CD117xCD3 TEA. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schliemann: Roche: Consultancy; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Other: travel grants; Boehringer-Ingelheim: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; AstraZeneca: Consultancy; Abbvie: Consultancy, Other: travel grants.
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- 2021
30. Intensified Cytarabine Dose during Consolidation Therapy in AML Patients Under 65 Years Is Not Associated with Survival Benefit
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Maher Hanoun, Johannes Kullmer, Christoph Schliemann, Andreas Neubauer, Mathias Haenel, Ulrich Kaiser, Sabrina Kraus, Gerhard Held, Hermann Einsele, Kerstin Schäfer-Eckhard, Tim H. Brümmendorf, Carsten Mueller-Tidow, Claudia D. Baldus, Christoph Röllig, Sebastian Scholl, Martin Goerner, Dirk Niemann, Michael Kramer, Hubert Serve, Uwe Platzbecker, Björn Steffen, Hans Christian Reinhardt, Martin Bornhaeuser, Stefan W. Krause, Tim Sauer, Martin Kaufmann, Ruth Seggewiss-Bernhard, Lars Fransecky, Leo Ruhnke, and Edgar Jost
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Consolidation therapy ,Survival benefit ,Internal medicine ,Cytarabine ,Medicine ,business ,medicine.drug - Abstract
Background: Acute myeloid leukemia (AML) is characterized by a high relapse rate, indicating insufficient clearance of leukemia-initiating cells. Depending on genetic risk stratification, consolidating chemotherapy proves to significantly reduce the risk of relapse. In particular, in younger AML patients higher dosage of cytarabine appears to improve long-term outcome, while there is no apparent benefit of multiagent combination, compared to cytarabine monotherapy. However, to this end the optimal dosage of single agent cytarabine in consolidation therapy after 7+3 remission induction remains elusive. Methods: Here, we retrospectively assessed the impact of different dosages of cytarabine consolidation on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020 with non-acute promyelocytic leukemia, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Results: 642 patients received HiDAC consolidation with a median dosage of 5794.88 (IQR, 4745.48-5971.56) mg/m 2/d with a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 1946.16 (IQR, 1869.51-2469.15) mg/m 2/d with a median of 2 cycles (IQR, 1-3). IDAC-treated patients showed in average a higher age (median (IQR) 58.5 (49-62) years vs. 50 (41-56) years) and more comorbidities with 43.8% having an HCT-CI score of 2-4, compared to 22.3% among HiDAC-treated patients. Alongside, significantly more secondary (5.1% vs. 3.1%) and therapy-related (12.4% vs. 4.1%) AML as well as more adverse (14.5% vs. 6.5%) and less favorable (40.6% vs. 56%) genetic risk features according to ELN 2017 risk classification were found among IDAC-treated patients. After propensity score weighting for differences in patient and disease characteristics, overall survival after 5 years was comparable between HiDAC-treated (71.1 %) and IDAC-treated (67.7%) patients. Moreover, no significant differences in relapse-free survival were observed after 5 years (47.4 vs. 45.2%). Notably, more patients treated with IDAC received allogeneic stem cell transplantation in first remission (37.6 vs. 19.8%) while significantly more HiDAC-treated patients underwent allogeneic stem cell transplantation in relapse (30.8 vs. 20.2%). Censoring for allogeneic stem cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only ELN favorable risk AML patients, there was no difference in 5-years overall (80.5% vs. 83.9%) nor relapse-free (57.7% vs. 56.8%) survival. Of note, significantly more patients treated with HiDAC suffered from ≥3 CTCAE infectious complications (56.7 vs. 44.1%), which was more striking in patients above 50 years of age. The rate of other ≥3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups. Conclusion: This retrospective analysis suggests no significant benefit of high dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. Disclosures Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.
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- 2021
31. Impact of Body Mass Index on Patient Outcome in Acute Myeloid Leukemia Patients Receiving Intensive Induction Therapy: A Real-World Registry Experience
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Maher Hanoun, Maxi Wass, Christoph Schliemann, Edgar Jost, Martin Kaufmann, Uwe Platzbecker, Sabrina Kraus, Mathias Haenel, Carsten Müller-Tidow, Markus Schaich, Sebastian Scheich, Stefan W. Krause, Sebastian Wolf, Christoph Röllig, Andreas Neubauer, Martin Bornhäuser, Julius Christoph Enssle, Sarah Weber, Tim Sauer, Michael Kramer, Jan-Henrik Mikesch, Leo Ruhnke, Dirk Niemann, Björn Steffen, Martina Crysandt, Andreas Burchert, Lars Fransecky, Ulrich Kaiser, Kerstin Schäfer-Eckhard, Claudia D. Baldus, Gerhard Held, Hans Christian Reinhardt, and Hubert Serve
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medicine.medical_specialty ,business.industry ,Internal medicine ,Induction therapy ,Immunology ,Medicine ,Myeloid leukemia ,Cell Biology ,Hematology ,business ,Biochemistry ,Outcome (game theory) ,Body mass index - Abstract
Acute myeloid leukemia (AML) is a hematologic malignancy that is treated in medically fit patients with intensive induction chemotherapy (IT) and postremission therapy to achieve a complete and long-term remission. The incidence of obesity in the general population is steadily increasing and has been identified as a major risk factor for all-cause mortality. Despite previous studies assessing the role of obesity in AML patients undergoing IT, there is an ongoing debate on the impact of obesity on patient outcome as well as the optimal dosing strategy in obese AML patients. We conducted a retrospective registry study assessing 1677 AML patients who were treated with IT for newly diagnosed AML. The primary endpoint was overall survival (OS) while event-free survival (EFS), the rate of first complete remission (CR1), relapse/refractory disease and non-relapse/refractory-related mortality (NRRrM), treatment-related toxicities, patient comorbidities and chemotherapy dosing strategies were analyzed as secondary endpoints. Obese patients (body mass index, BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, p = 0.015) without a significant difference in median EFS (7.8 vs. 9.89 months, p = 0.3) compared to non-obese patients (BMI < 30). The cumulative incidence (CI) of NRRrM was significantly increased in obese patients compared to non-obese patients while no differences could be observed regarding the CI of relapsed or refractory disease. Obesity was identified as an independent risk factor for death (HR 1.27, [95% CI 1.07-1.51], p = 0.005) in a multivariable Cox regression analysis. When the cohort was stratified by age (≥/< 60 years), the difference in OS as well as the significantly increased CI of NRRrM was only observed in patients ≥ 60 years. Notably, obese patients demonstrated higher rates of cardiovascular and metabolic comorbidities regardless of their age. No disparities for OS, EFS, CR1 rate or treatment-related toxicities were observed when the entire study population was stratified for the used dosing strategy (dose calculation using total body weight, idealized body weight, adjusted idealized body weight or capped at body surface area of 2 m 2). In conclusion, the present study identifies obesity as a major independent risk factor for worse overall survival and increased CI of non-relapse/refractory-related mortality in older (≥60 years) AML patients undergoing curative IT. These findings may be most likely attributed to obesity related comorbidities and not to dose adaption of chemotherapy in obese AML patients. Disclosures Schliemann: Boehringer-Ingelheim: Research Funding; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fransecky: Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Medac: Honoraria; Takeda: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Platzbecker: Celgene/BMS: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Baldus: Jazz: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria.
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- 2021
32. Diagnostic Red Blood Cell Distribution Width As a Prognostic Factor in Acute Myeloid Leukemia
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Vladan Vucinic, Leo Ruhnke, Katja Sockel, Maximilian Alexander Röhnert, Donata Backhaus, Dominic Brauer, Georg-Nikolaus Franke, Dietger Niederwieser, Martin Bornhäuser, Christoph Rollig, Uwe Platzbecker, Sebastian Schwind, and Madlen Jentzsch
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction: A high red blood cell distribution width (RDW) mirrors dysregulated erythrocyte homeostasis and is associated with a higher mortality in several solid cancers and myelodysplastic syndrome (MDS). A high RDW may also identify individuals more likely to develop a MDS or an acute myeloid leukemia (AML). The prognostic relevance of the RDW in patients diagnosed with AML has not been previously evaluated. Methods: We analyzed 294 newly diagnosed AML patients (median age at diagnosis 61, range 14-77 years [y]) that underwent an allogeneic hematopoietic stem cell transplantation (HSCT) at the University Hospital Leipzig in complete remission (CR, 63%), CR with incomplete peripheral recovery (CRi, 18%) or with active disease (19%). The RDW was measured at diagnosis and a cut-off of 20.7% was determined using the R package "OptimalCutpoints" to define patients with a low (87%) or high (13%) diagnostic RDW. Disease risk was assessed according to European LeukemiaNet (ELN) 2017. Median follow up after HSCT was 3.0 y. To verify the results irrespective of the consolidating therapy, a validation set of 392 AML patients (median age at diagnosis 63, range 18-87 years) treated at the University Hospital Dresden was analyzed. Here, 46% of patients received chemotherapy alone and patients that underwent allogeneic HSCT were censored at the time of HSCT. Results: The diagnostic RDW was above the local upper limit of normal (> 15%) in the majority (73%) of AML patients. The RDW as continuous parameter was higher in patients with AML developing from an antecedent myeloid disorder (sAML, after MDS, MPN, or MDS/MPN) than in patients with de novo (P=.01) or treatment-related AML (tAML, after lymphatic or solid neoplasm, P=.02, Figure 1A). A higher RDW was also observed in patients harboring gene mutations previously linked to AML of secondary origin (i.e. mutated JAK2 [P=.03], ASXL1 [P=.004], or spliceosome mutation [P=.03, compromising SF3B1, SRSF2, U2AF1, and ZRSR2, Figure 1B], which was particularly driven by SRSF2 mutations [P=.002]). Adapting an optimal cut, a higher RDW (> 20.7%) was associated with a higher non-relapse mortality (NRM, P=.02), shorter overall survival (OS, P=.009, Figure 1C), but similar relapse incidence (P=.96). In multivariate analyses, the RDW retained its prognostic significance for a higher NRM after adjustment for age at diagnosis. A RDW > 20.7% was also associated with lower hemoglobin levels at diagnosis and a trend for lower incidence of NPM1 mutations (P=.06), which are enriched in de novo AML. In contrast, RDW levels were not associated with chromosomal abnormalities (P=.72) or ELN2017 disease risk (P=.55). Despite known association of a high RDW with a higher cardiovascular/inflammatory risk, neither the comorbidity index at HSCT (HCT-CI, P=.77) nor the incidence of an acute (P=1) or chronic (P=.63) graft-versus-host disease differed according to the diagnostic RDW. Comparably, in the validation set, higher RDW levels were observed in patients with sAML compared to de novo (P=.02) or tAML (P=.02). Introducing the established 20.7% cut into the validation set, patients with high RDW levels again had lower hemoglobin levels at diagnosis (P Conclusions: Our study is the first to evaluate the diagnostic RDW in AML patients. Patients with a secondary AML or secondary AML-associated gene mutations had higher diagnostic RDW levels. The presence of a high diagnostic RDW identifies patients with worse outcomes, irrespective of the ELN2017 risk classification and the applied consolidation therapy. This cost-effective and fast to assess parameter may help to personalize AML patient treatment. Figure 1 Figure 1. Disclosures Vucinic: Gilead: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; MSD: Honoraria; Abbvie: Honoraria, Other: Travel Sponsoring; Janssen: Honoraria, Other: Travel Sponsoring. Backhaus: Bayer: Other: Current Employment of Family Member. Franke: BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Schwind: Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Jentzsch: Astellas: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.
- Published
- 2021
33. Abstract 821: Comprehensive genomic analysis of rare cancers: Results of the MASTER precision oncology trial of the German Cancer Consortium
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Jens T. Siveke, Melanie Boerries, Thomas Kindler, Hanno Glimm, Jennifer Hüllein, Daniel Hübschmann, Christoph Heining, Barbara Hutter, Barbara Klink, Anna Lena Illert, Klaus Schulze-Osthoff, Laura Gieldon, Stephan Wolf, Martina Fröhlich, Evelin Schröck, Sebastian Ochsenreither, Albrecht Stenzinger, Stefan Frohling, Christof von Kalle, Christoph E. Heilig, Bettina Meissburger, Peter Schirmacher, Sebastian Bauer, Andreas Mock, Sebastian Uhrig, Katja Beck, Daniela Richter, Andreas Lassmann, U. Keilholz, Christina Geörg, G. Folprecht, Michael Bitzer, Wilko Weichert, Arne Jahn, Richard F. Schlenk, Simon Kreutzfeldt, Christian Brandts, Karsten Spiekermann, Leo Ruhnke, Nikolas von Bubnoff, Dorothea Hanf, Philipp J. Jost, Peter Horak, Veronica Teleanu, Katrin Pfütze, Lino Möhrmann, Frederick Klauschen, and Benedikt Brors
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,medicine.disease ,language.human_language ,German ,Precision oncology ,Internal medicine ,language ,medicine ,business - Abstract
Comprehensive molecular profiling can be successfully applied to guide targeted treatment in cancer patients, an approach commonly referred to as precision oncology. Over the past years, several clinical trials that employed subgenomic molecular profiling have demonstrated that molecularly informed decision-making across tumor entities is associated with improved clinical outcome in approximately one third of patients. To investigate the feasibility and clinical relevance of comprehensive genomic analysis, i.e. whole-exome/genome sequencing (WES/WGS) and RNA sequencing (RNA-seq), in younger adults with advanced-stage cancer across all histologies and patients with rare tumors, we established MASTER (Molecularly Aided Stratification for Tumor Eradication Research) - a prospective, multicenter precision oncology platform - at NCT Heidelberg/Dresden in 2013, which was extended to the German Cancer Consortium (DKTK) in 2016. Based on a standardized workflow, we have analyzed more than 1,700 poor-prognosis (median overall survival, 12 months) patients with advanced, heavily pretreated (median number of prior therapies, n=2) malignancies representing a broad spectrum of rare histopathologic entities. We here report the actionable findings and clinical outcomes for the first 1,311 patients discussed in cross-institutional molecular tumor board (MTB) conferences. Each MTB recommendation was based on the individual molecular profile and specific predictive molecular biomarkers identified by WES/WGS and RNA-seq. In addition to DNA alterations (single-nucleotide variants, small insertions/deletions, copy number alterations), we also used alterations identified by RNA-seq (gene fusions, aberrant gene expression) to support clinical decision-making. We categorized therapy recommendations into seven different intervention baskets and assigned evidence levels to each recommendation according to a dedicated NCT/DKTK classification system, which addresses the complexity of evaluating predictive molecular biomarkers in clinical routine. MTB recommendations were implemented in one third of cases, and overall response and disease control rates on molecularly guided treatment were improved compared to prior systemic therapies, which translated into a progression-free survival ratio of greater than 1.3 in a significant proportion of patients. Furthermore, comprehensive genomic profiling in combination with histopathologic reevaluation allowed reclassification of approximately 4% of cases, in particular soft-tissue sarcomas not otherwise specified and carcinomas of unknown primary site. This prospective study demonstrates that comprehensive molecular profiling based on WES/WGS and RNA-seq in a multiinstitutional clinical setting creates meaningful therapeutic opportunities for patients with rare cancers. Our data demonstrate the added benefit of germline and RNA analysis, providing a rationale for their routine clinical implementation. Current and future activities of the MASTER network are focused on the standardization of variant classification and evidence levels in MTB conferences, the implementation of molecularly stratified basket trials, and the integration of additional layers of patient characterization. Citation Format: Peter Horak, Christoph Heining, Andreas Mock, Simon Kreutzfeldt, Andreas Lassmann, Lino Möhrmann, Jennifer Hüllein, Dorothea Hanf, Arne Jahn, Leo Ruhnke, Laura Gieldon, Christoph E. Heilig, Veronica Teleanu, Martina Fröhlich, Sebastian Uhrig, Katja Beck, Daniela Richter, Stephan Wolf, Katrin Pfütze, Christina Geörg, Bettina Meissburger, Frederick Klauschen, Ulrich Keilholz, Sebastian Ochsenreither, Gunnar Folprecht, Jens Siveke, Sebastian Bauer, Thomas Kindler, Christian Brandts, Melanie Boerries, Anna L. Illert, Nikolas von Bubnoff, Karsten Spiekermann, Philipp J. Jost, Klaus Schulze-Osthoff, Michael Bitzer, Peter Schirmacher, Christof von Kalle, Richard F. Schlenk, Barbara Klink, Barbara Hutter, Daniel Hübschmann, Albrecht Stenzinger, Wilko Weichert, Evelin Schröck, Benedikt Brors, Hanno Glimm, Stefan Fröhling, German Cancer Consortium (DKTK). Comprehensive genomic analysis of rare cancers: Results of the MASTER precision oncology trial of the German Cancer Consortium [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 821.
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- 2020
34. Mutant TET2 Allele Dosage Affects Response to 5-Azacitidine in Acute Myeloid Leukemia
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Torsten Haferlach, Manja Meggendorfer, Kenan Onel, Mohd Fadly, Emmanouela-Niki Soura, Manja Wobus, Daniel Allsop, Helen J. Blair, Sarah E. Fordham, Claire Elstob, Thahira Rahman, Martin Bornhäuser, Devi Nandana, Catherine Park, Gail Jones, Desiree Kunadt, Olaf Heidenreich, Tobias Menne, Wei-Yu Lin, Helen Marr, Friedrich Stoelzel, Brigitte Mohr, Leo Ruhnke, Graham Jackson, James M. Allan, and Heidi Altmann
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Biallelic Mutation ,Immunology ,Nonsense mutation ,Mutant ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Uniparental disomy ,Leukemia ,Monoallelic Mutation ,Mutation (genetic algorithm) ,medicine ,Cancer research - Abstract
Personalised medicine is predicted to significantly improve outcomes for cancer patients, but implementation requires comprehensive genetic characterisation of malignant cells to identify therapeutically exploitable vulnerabilities. Using an isogenic cell model system with CRISPR-inactivated TET2 in HEL acute myeloid leukemia (AML) cells and an orthotopic mouse xenograft model we demonstrate that mutant TET2 allele dosage significantly affects sensitivity to 5-azacitidine hypomethylating therapy in AML, with biallelic mutation conferring hypersensitivity relative to monoallelic mutation. In the presence of 5-azacitidine, cell clones with biallelic TET2 mutation had significantly lower cloning efficiency (P = 3 x 10-3) and proliferation in liquid culture (P < 1 x 10-4) compared to isogenic clones with monoallelic TET2 mutation. Mixed populations of monoallelic and biallelicTET2 mutated HEL AML cells were transplanted via intrafemoral injection into Rag2−/−Il2rg−/−129×Balb/c mice, and treatment with 5-azacitidine resulted in significant negative in vivo selection against TET2 null cells relative to cells with monoallelic TET2 mutation (P = 4 x 10-4). Methylation analysis revealed the acquisition of an overall hypermethylation phenotype in TET2 null cells and RNA sequencing identified significant down-regulation of ABCB1 transcript, resulting in concomitant pronounced down-regulation of the MDR1 drug efflux transporter at the protein level. RNA sequencing pathway analysis also identified a global effect on ribosome pathway (KEGG pathway ko03010) transcript levels (Padjusted = 0.002), evidenced by down-regulation of numerous RNA polymerase II components in cells with bi-allelic TET2 mutation compared to cells with monoallelic TET2 mutation. Consistent with our isogenic model data, we characterise biallelic somatic TET2 mutation in a patient with AML that was chemoresistant to anthracycline/cytarabine-based chemotherapy but acutely sensitive to 5-azacitidine, resulting in durable cytomorphological remission. Integration of next generation sequencing, interphase FISH and SNP array analysis of bone marrow at AML presentation, relapse and during remission was used to infer tumour phylogeny which indicated that disease pathogenesis was initiated by a TET2 nonsense mutation (c.2815C>T, Q939*) with subsequent deletion of the second TET2 allele and a NPM1 mutation (c.863_864ins, TCTG) that arose after the acquisition of bi-allelic TET2 mutation. Furthermore, our data demonstrate that 5-azacitidine treatment almost completely eliminated the TET2/NPM1-mutated clone. 5-azacitidine also induced a modest reduction in ancestral pre-leukemic cells carrying bi-allelic TET2 mutation but negative for the NPM1 mutation, although the majority retained viability and re-acquired the ability to differentiate and recapitulate normal haematopoiesis rendering a cytomorphological remission. These observations suggest that bi-allelic TET2 mutation confers sensitivity to the cytotoxic effects of 5-azacitidine, but that the major effect of 5-azacitidine is the induction of phenotypic re-programming. The frequency of TET2 mutation in primary AML is estimated at 10-20%, with the majority of these being monoallelic. We determined the frequency of TET2 alterations in AML patients presenting with a chromosome 4 abnormality discernible cytogenetically. TET2 copy number and mutational status were determined using high density SNP arrays and gene sequencing, respectively. In a panel of 30 AML cases with a chromosome 4 abnormality, four patients were heterozygous for TET2 mutation (all deletions resulting in reduced copy number) and three patients were homozygous for TET2 mutation (deletion plus base substitution in two cases and homozygous base substitution resulting from uniparental disomy in one case). Furthermore, all seven cases with TET2 mutation were characterised by cytogenetics that included loss or gain of material on chromosome 4. In contrast, only 1 case with a TET2 mutation had a translocation affecting chromosome 4. In summary, our data argue in favour of using 5-azacitidine in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of personalised medicine for cancer patients. Disclosures Stoelzel: JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
- Published
- 2019
35. New automatic quantification method of immunofluorescence and histochemistry in whole histological sections
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Anne Steglich, Florian Gembardt, Julian Stumpf, Friederike Kessel, Christian M. Cohrs, Irakli Kopaliani, Rayk Behrendt, Michael Gerlach, Vladimir T. Todorov, Christian Hugo, Todor Tschongov, and Leo Ruhnke
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0301 basic medicine ,Staining and Labeling ,medicine.diagnostic_test ,Software tool ,Fluorescent Antibody Technique ,Cell Biology ,Open source software ,Limiting ,Computational biology ,Biology ,Kidney ,Immunofluorescence ,Imaging data ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Humans ,Immunohistochemistry ,Algorithms ,Software ,Fluorescent Dyes - Abstract
Immunofluorescent staining is a widespread tool in basic science to understand organ morphology and (patho-) physiology. The analysis of imaging data is often performed manually, limiting throughput and introducing human bias. Quantitative analysis is particularly challenging for organs with complex structure such as the kidney. In this study we present an approach for automatic quantification of fluorescent markers and histochemical stainings in whole organ sections using open source software. We validate our novel method in multiple typical challenges of basic kidney research and demonstrate its general relevance and applicability to other complex solid organs for a variety of different markers and stainings. Our newly developed software tool “AQUISTO”, applied as a standard in primary data analysis, facilitates efficient large scale evaluation of cellular populations in various types of histological samples. Thereby it contributes to the characterization and understanding of (patho-) physiological processes.
- Published
- 2019
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