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16 results on '"Hilgendorf, Inken"'

1. Treosulfan compared with <scp>reduced‐intensity</scp> busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial

Author

Beelen, Dietrich, Stelljes, Matthias, Reményi, Péter, Wagner‐Drouet, Eva‐Maria, Dreger, Peter, Bethge, Wolfgang, Ciceri, Fabio, Stölzel, Friedrich, Junghanß, Christian, Labussiere‐Wallet, Hélène, Schaefer‐Eckart, Kerstin, Grigoleit, Goetz U., Scheid, Christof, Patriarca, Francesca, Rambaldi, Alessandro, Niederwieser, Dietger, Hilgendorf, Inken, Russo, Domenico, Socié, Gérard, Holler, Ernst, Glass, Bertram, Casper, Jochen, Wulf, Gerald, Basara, Nadezda, Bieniaszewska, Maria, Stuhler, Gernot, Verbeek, Mareike, La Rocca, Ursula, Finke, Jürgen, Benedetti, Fabio, Pichlmeier, Uwe, Klein, Anja, Baumgart, Joachim, Markiewicz, Miroslaw, and Rocca, Ursula La

Subjects
Leukemia, Myeloid, Acute, Transplantation Conditioning, Myelodysplastic Syndromes, Medizin, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Humans, Prospective Studies, Hematology, Middle Aged, Busulfan, Vidarabine, Aged
Abstract

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged >= 50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m(2) IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.

Published
2022

2. Impfen bei Immundefizienz

Author

Laws, Hans-Jürgen, Baumann, Ulrich, Bogdan, Christian, Burchard, Gerd, Christopeit, Maximilian, Hecht, Jane, Heininger, Ulrich, Hilgendorf, Inken, Kern, Winfried, Kling, Kerstin, Kobbe, Guido, Külper, Wiebe, Lehrnbecher, Thomas, Meisel, Roland, Simon, Arne, Ullmann, Andrew, de Wit, Maike, and Zepp, Fred

Subjects
Bekanntmachungen – Amtliche Mitteilungen
Published
2020

3. Additional file 1 of Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

Author

Kunadt, Desiree, Stasik, Sebastian, Metzeler, Klaus H., Röllig, Christoph, Schliemann, Christoph, Greif, Philipp A., Spiekermann, Karsten, Rothenberg-Thurley, Maja, Krug, Utz, Braess, Jan, Krämer, Alwin, Hochhaus, Andreas, Scholl, Sebastian, Hilgendorf, Inken, Brümmendorf, Tim H., Jost, Edgar, Steffen, Björn, Bug, Gesine, Einsele, Hermann, Görlich, Dennis, Sauerland, Cristina, Schäfer-Eckart, Kerstin, Krause, Stefan W., Hänel, Mathias, Hanoun, Maher, Kaufmann, Martin, Wörmann, Bernhard, Kramer, Michael, Sockel, Katja, Egger-Heidrich, Katharina, Herold, Tobias, Ehninger, Gerhard, Burchert, Andreas, Platzbecker, Uwe, Berdel, Wolfgang E., Müller-Tidow, Carsten, Hiddemann, Wolfgang, Serve, Hubert, Stelljes, Matthias, Baldus, Claudia D., Neubauer, Andreas, Schetelig, Johannes, Thiede, Christian, Bornhäuser, Martin, Middeke, Jan M., and Stölzel, Friedrich

Abstract

Additional file 1: Table S1 Overview of the clinical trials the study patients were selected from. Figure S1 Forrest Plot of variables evaluated in univariate analysis. Multivariate Cox proportional hazard regression for (A) overall survival and (B) relapse-free survival.

Published
2022
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4. Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

Author

Kunadt, Desiree, Stasik, Sebastian, Metzeler, Klaus H., Röllig, Christoph, Schliemann, Christoph, Greif, Philipp A., Spiekermann, Karsten, Rothenberg-Thurley, Maja, Krug, Utz, Braess, Jan, Krämer, Alwin, Hochhaus, Andreas, Scholl, Sebastian, Hilgendorf, Inken, Brümmendorf, Tim H., Jost, Edgar, Steffen, Björn, Bug, Gesine, Einsele, Hermann, Görlich, Dennis, Sauerland, Cristina, Schäfer-Eckart, Kerstin, Krause, Stefan W., Hänel, Mathias, Hanoun, Maher, Kaufmann, Martin, Wörmann, Bernhard, Kramer, Michael, Sockel, Katja, Egger-Heidrich, Katharina, Herold, Tobias, Ehninger, Gerhard, Burchert, Andreas, Platzbecker, Uwe, Berdel, Wolfgang E., Müller-Tidow, Carsten, Hiddemann, Wolfgang, Serve, Hubert, Stelljes, Matthias, Baldus, Claudia D., Neubauer, Andreas, Schetelig, Johannes, Thiede, Christian, Bornhäuser, Martin, Middeke, Jan M., and Stölzel, Friedrich

Subjects
Leukemia, Myeloid, Acute, Cancer Research, Oncology, Mutation, Medizin, Hematopoietic Stem Cell Transplantation, Humans, Hematology, ddc:610, Prognosis, Nucleophosmin, Molecular Biology, Isocitrate Dehydrogenase
Abstract

Journal of hematology & oncology 15, 126 (2022). doi:10.1186/s13045-022-01339-8, Published by Biomed Central, London

Published
2022
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5. Comparison of Cytomegalovirus-Specific Immune Cell Response to Proteins versus Peptides Using an IFN-γ ELISpot Assay after Hematopoietic Stem Cell Transplantation

Author

Wolff, Daniel, Wagner-Drouet, Eva Maria, Teschner, Daniel, Wolschke, Christine, Schäfer-Eckart, Kerstin, Gärtner, Johannes, Mielke, Stephan, Schreder, Martin, Kobbe, Guido, Hilgendorf, Inken, Klein, Stefan, Verbeek, Mareike, Ditschkowski, Markus, Koch, Martina, Lindemann, Monika, Schmidt, Traudel, Rascle, Anne, Barabas, Sascha, Deml, Ludwig, and Wagner, Ralf

Subjects
ddc:610, lcsh:R5-920, immune monitoring, immunosuppression, 610 Medizin, Medizin, CMV, T cells, CMV-specific cellular immunity, hematopoietic stem cell transplantation, recall antigen, peptide, IFN-γ ELISpot, antigen processing and presentation, virus diseases, Article, lcsh:Medicine (General)
Abstract

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8+ counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.

Published
2021

6. Post-transplant multimorbidity index and quality of life in patients with chronic graft-versus-host disease—results from a joint evaluation of a prospective German multicenter validation trial and a cohort from the National Institutes of Health

Author

Wolff, Daniel, Herzberg, Philipp Y., Herrmann, Anne, Pavletic, Steven Z., Heussner, Pia, Mumm, Friederike, Höfer, Christina, Hilgendorf, Inken, Hemmati, Philipp G., Holler, Ernst, and Greinix, Hildegard

Subjects
ddc:610, immune system diseases, 610 Medizin
Abstract

Comorbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT) impairs quality of life (QoL), physical functioning, and survival. We developed a new standardized measure to capture comorbidity after transplantation, the Posttransplant Multimorbidity Index (PTMI) in a cohort of 50 long term survivors. We subsequently evaluated the content validity and impact on survival and QoL within a multicenter trial, including 208 patients (pts) after alloHSCT, who were prospectively evaluated applying the FACT-BMT, the Human Activity Profile (HAP), the SF-36 v.2, PTMI and the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). The most prevalent comorbidities were compensated arterial hypertension (28.4%), ambulatory infections (25.5%), iron overload (23%), mild renal function impairment (20%), and osteoporosis (13%). Applying the PTMI 13% of patients had no comorbidity, while 37.1% had 1–3 comorbidities, 27.4% had 4–6 comorbidities, and 13.5% had > 6 comorbidities. Chronic graft-versus-host disease (cGvHD) was significantly associated with the PTMI, while age and prior acute GvHD were not. In contrast, the HCT-CI was not associated with the presence of cGvHD. cGvHD was significantly associated with depression (r = 0.16), neurological disease (r = 0.21), osteoporosis (r = 0.18) and nonmelanoma skin cancer (r = 0.26). The PTMI demonstrated strong measurement properties and compared to the HCT-CI captured a wider range of comorbidities associated with cGvHD.

Published
2020

7. Final Results of a Prospective, Multicenter, noninterventional Study on thiotepa-based Autologous Hematopoietic Cell Transplantation (ASCT) for CNS or non-CNS Lymphoma

Author

Sayer, Herbert Gottfried, Witzens-Harig, Mathias, Wattad, Mohammad, Korfel, Agnieszka, Hilgendorf, Inken, Franke, Georg-Nikolaus, Illerhaus, Gerald, Heinsch, Michael, Metzner, Bernd, Zinngrebe, Eva Bettina, Binder, Mascha, Ringhoffer, Mark, Röth, Alexander, Geer, Thomas, Schmidt, Volker, and Dreger, Peter

Subjects
Medizin, ComputingMethodologies_GENERAL
Abstract

Poster-Abstract

Published
2020

8. Erratum : Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Mathew, Nimitha R, Baumgartner, Francis, Braun, Lukas, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Markus, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst, Thomas, Schroeder, Thomas, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandros, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-de-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yves, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolaus, Ayuk, Francis, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, van der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andreas, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, McLornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Shah, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andreas, Neubauer, Andreas, Beelen, Dietrich, Mackensen, Andreas, von Bubnoff, Nikolas, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justus, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert

Abstract

This corrects the article DOI: 10.1038/nm.4484.

Published
2018

9. Thiotepa-based Autologous hematopoietic stem cell transplantation (ASCT) for CNS or non-CNS lymphoma : first results of a prospective, multicenter, non-interventional study

Author

Sayer, Herbert G., Witzens-Harig, Mathias, Wattad, Mohammed, Korfel, Agnieszka, Hilgendorf, Inken, Franke, Georg-Nikolaus, Illerhaus, Gerald, Heinsch, Michael, Metzner, Bernd, Zinngrebe, Eva Bettina, Basara, Nadezda, Binder, Mascha, Schmidt, Volker, Ringhoffer, Mark, Röth, Alexander, Geer, Thomas, and Dreger, Peter

Subjects
Medizin
Published
2018

10. Treosulfan conditioning for allogenic hematopoietic stem cell transplantation in multiple myeloma, advantages for non-relapse mortality and survival, but with high incidence of relapse

Author

Gran, Charlotte, Wang, Junfeng, Nahi, Hareth, Koster, Linda, Einsele, Herman, Itälä-Remes, Maija, Holler, Ernst, Beelen, Dietrich, Ciceri, Fabio, Ehninger, Gerhard, Finke, Jürgen, de Wreede, Liesbeth, Ljungman, Per, Tischer, Johanna, Verbeek, Mareike, Klyuchnikov, Evgeny, Hilgendorf, Inken, Schäfer-Eckart, Kerstin, Scheid, Christof, Bunjes, Donald, Basara, Nadezda, Haenel, Mathias, Müller, Lutz Peter, Biersack, Harald, Gahrton, Gösta, Garderet, Laurent, and Kröger, Nicolaus

Subjects
Medizin
Published
2018

11. Personality influences quality of life assessments in adult patients after allogeneic hematopoietic stem cell transplantation – Results from a joint evaluation of the prospective German Multicenter Validation Trial and the Fred Hutchinson Cancer Research Center

Author

Herzberg, Philipp Y., Lee, Stephanie J., Heussner, Pia, Mumm, Friederike H.A., Hilgendorf, Inken, von Harsdorf, Stephanie, Hemmati, Philipp, Rieger, Kathrin, Greinix, Hildegard T., Freund, Mathias, Holler, Ernst, and Wolff, Daniel

Subjects
Adult, Neuroticism, Washington, Adolescent, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Middle Aged, Anxiety Disorders, Personality Disorders, Severity of Illness Index, Article, Cohort Studies, Young Adult, Austria, Germany, Hematologic Neoplasms, Activities of Daily Living, Quality of Life, Humans, Transplantation, Homologous, Longitudinal Studies, Prospective Studies, Aged, Follow-Up Studies, Personality
Abstract

The influence of personality on health related quality of life (QoL) and physical functioning in the setting of allogeneic hematopoietic SCT (alloHSCT) is unknown. We conducted a joint evaluation within two independent cohorts of alloHSCT recipients to investigate the impact of personality on reported QoL and physical functioning. Two-hundred-eight patients (median age 44 years, range 18-72) of cohort 1 and 93 patients (median age 55 years, range 19-79) of cohort 2 after alloHSCT were evaluated. Personality was assessed using the 24-adjective measure (AM), which measures the Big-Five personality domains and the Life Orientation Test-Revised (LOT-R), measuring optimism and pessimism. QoL was measured using the Functional Assessment of Cancer Therapy with bone marrow transplantation subscale (FACT-BMT), Short Form 36 (SF-36), the human activity profile (HAP), as well as the NIH criteria-based cGVHD activity assessment form and the Lee cGVHD symptom scale. Neuroticism was significantly associated with worse function measured by the HAP and FACT-BMT. Optimism significantly improved QoL captured by the FACT-BMT. Pessimism significantly impaired physical function captured by the HAP and SF-36. Extraversion was significantly associated with reduced depression and lower severity of cGVHD symptoms reported by the patient and the physician. The results suggest that personality traits and pre-treatment QoL assessments should be measured in clinical trials to facilitate the interpretation of QoL data.

Published
2012

12. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Mathew, Nimitha R, Baumgartner, Francis, Braun, Lukas, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Markus, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst Müller, Thomas Niklaus, Schroeder, Thomas, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandros, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-De-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yves, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolaus, Ayuk, Francis, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, Van Der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andreas, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, McLornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Shah, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andreas, Neubauer, Andreas, Beelen, Dietrich, Mackensen, Andreas, Von Bubnoff, Nikolas, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justus, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert

Subjects
hemic and lymphatic diseases, 610 Medicine & health, neoplasms, 3. Good health
Abstract

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

13. Clinical validation of a novel ELISpot-based in vitro diagnostic assay to monitor CMV-specific cell-mediated immunity in hematopoietic stem cell transplant recipients

Author

Wagner, Eva, Daniel Teschner, Wolschke, Christine, Jason, Dietlinde, Schaefer-Eckart, Kerstin, Gaertner, Johannes, Mielke, Stephan, Schreder, Martin, Kobbe, Guido, Kondakci, Mustafa, Klein, Stefan, Heidenreich, Daniela, Kreil, Sebastian, Hilgendorf, Inken, Lilienfeld-Toal, Marie, Verbeek, Mareike, Grass, Sandra, Ditschkowski, Markus, Gromke, Tanja, Koch, Martina, Huenig, Thomas, Lindemann, Monika, Schmidt, Traudel, Rascle, Anne, Barabas, Sascha, Deml, Ludwig, Wagner, Ralf, and Wolff, Daniel

Subjects
Medizin

14. Chemo-Immuntherapie in einem präklinischen MLH1-knockout Modell

Author

Wiegele, Leonie, Maletzki, Claudia, Hilgendorf, Inken, Stintzing, Sebastian Jörg, and Universitätsmedizin Rostock.

Subjects
610 Medical sciences Medicine, ddc:610
Abstract

Die MMR-D liegt zwei hereditären Krankheitsbildern, dem Lynch Syndrom (monoallelisch) und der konstitutionellen MMR-D (biallelisch), zugrunde. Aufgrund der hohen Immunogenität stellen diese Tumoren ideale Zielstrukturen für immuntherapeutische Interventionen dar. Anhand des MLH1-knockout Modells wurde die Wirksamkeit einer kombinierten Chemo-Immuntherapie eruiert. Es zeigte sich, dass die Tumorinzidenz und das -wachstum sowohl prophylaktisch als auch therapeutisch verzögert wurden, bedingt durch die positive Modulation des Immunsystems und die transiente Reduktion immunsuppressiver Zellen.

Published
2020

15. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Author

Donald Bunjes, Sebastian Halbach, Dietmar Pfeifer, Philipp Hemmati, Robert S. Negrin, Fabio Ciceri, Jean-Yves Cahn, Markus Ditschkowski, Pavan Reddy, Kathrin Hanke, Daniela Dörfel, Susan Klaeger, Jürgen Finke, Zehan Hu, Gabriele Ihorst, Gérard Socié, Sanaz Taromi, Andreas Hochhaus, Glen A Kennedy, Omid Shah, Andreas Neubauer, Robert Thimme, Michael Schultheiss, Sabine Spath, Dietrich W. Beelen, Sandra Duquesne, Arnim Weber, Geoffrey R. Hill, Ronjon Chakraverty, Jürgen Kuball, Guido Kobbe, Nikolas von Bubnoff, Andrea S. Henden, Betul Oran, Burkhard Becher, Bernhard Kuster, Christoph Rummelt, Lena Osswald, Hartmut Bertz, Wolfgang Bethge, Eva-Maria Wagner, Arnon Nagler, Eliana Ruggiero, Saar Gill, Miguel Waterhouse, Andreas Mackensen, Dominik Bettinger, Francis Baumgartner, Florian Kuchenbauer, Anita Sarma, Takanori Teshima, Erika L. Pearce, Antonia M.S. Müller, Kathleen Stabla, John M. Magenau, Evelyn Ullrich, Nicolaus Kröger, Georg Häcker, Simone Thomas, Myriam Labopin, Ghulam J. Mufti, Jan E. Ehlert, Lutz P. Müller, Marie Follo, Dominik Wolf, Tony Andreas Müller, Michael Lübbert, Jacqueline Schnell, Christof Scheid, Takeshi Kondo, Donal P. McLornan, Thomas Pabst, Konrad Wilhelm, Chiara Bonini, Wolf Rösler, Simon Richardson, Cordula A. Jilg, Andrea Schmidts, Luca Vago, Joseph H. Antin, Annette Schmitt-Graeff, Yakup Tanriver, Michael A. Caligiuri, Wolfgang Herr, Kai-Li Yan, Lukas Braun, Daniel J. Weisdorf, Katayoun Rezvani, Giang Lam Vuong, Tilman Brummer, Stephan Meckel, Ralph Wäsch, Geoffroy Andrieux, Soroush Doostkam, Hauke Busch, Dennis Dong Hwan Kim, Sabine Gerull, Bruce R. Blazar, Robert Zeiser, Merav Bar, Flore Sicre-de-Fontbrune, Daniel Feger, Melanie Börries, Wolfgang Melchinger, Petya Apostolova, C. Leiber, Udo Holtick, Walter J.F.M. van der Velden, Renate Arnold, Rainer Claus, Justus Duyster, Nimitha R. Mathew, David O’Sullivan, Alexandros Spyridonidis, S K Metzelder, Thomas Schroeder, Jörg Halter, Johanna Haag, Friedrich Stölzel, Christoph Schmid, Anna Lena Illert, Claudia Lengerke, Björn Hackanson, Joern Dengjel, Francis Ayuk, Rainer Ordemann, Sonia Tugues, Marco Prinz, Inken Hilgendorf, Andreas Burchert, Mathew, Nimitha R, Baumgartner, Franci, Braun, Luka, O'Sullivan, David, Thomas, Simone, Waterhouse, Miguel, Müller, Tony A, Hanke, Kathrin, Taromi, Sanaz, Apostolova, Petya, Illert, Anna L, Melchinger, Wolfgang, Duquesne, Sandra, Schmitt-Graeff, Annette, Osswald, Lena, Yan, Kai-Li, Weber, Arnim, Tugues, Sonia, Spath, Sabine, Pfeifer, Dietmar, Follo, Marie, Claus, Rainer, Lübbert, Michael, Rummelt, Christoph, Bertz, Hartmut, Wäsch, Ralph, Haag, Johanna, Schmidts, Andrea, Schultheiss, Michael, Bettinger, Dominik, Thimme, Robert, Ullrich, Evelyn, Tanriver, Yakup, Vuong, Giang Lam, Arnold, Renate, Hemmati, Philipp, Wolf, Dominik, Ditschkowski, Marku, Jilg, Cordula, Wilhelm, Konrad, Leiber, Christian, Gerull, Sabine, Halter, Jörg, Lengerke, Claudia, Pabst, Thoma, Schroeder, Thoma, Kobbe, Guido, Rösler, Wolf, Doostkam, Soroush, Meckel, Stephan, Stabla, Kathleen, Metzelder, Stephan K, Halbach, Sebastian, Brummer, Tilman, Hu, Zehan, Dengjel, Joern, Hackanson, Björn, Schmid, Christoph, Holtick, Udo, Scheid, Christof, Spyridonidis, Alexandro, Stölzel, Friedrich, Ordemann, Rainer, Müller, Lutz P, Sicre-de-Fontbrune, Flore, Ihorst, Gabriele, Kuball, Jürgen, Ehlert, Jan E, Feger, Daniel, Wagner, Eva-Maria, Cahn, Jean-Yve, Schnell, Jacqueline, Kuchenbauer, Florian, Bunjes, Donald, Chakraverty, Ronjon, Richardson, Simon, Gill, Saar, Kröger, Nicolau, Ayuk, Franci, Vago, Luca, Ciceri, Fabio, Müller, Antonia M, Kondo, Takeshi, Teshima, Takanori, Klaeger, Susan, Kuster, Bernhard, Kim, Dennis Dong Hwan, Weisdorf, Daniel, van der Velden, Walter, Dörfel, Daniela, Bethge, Wolfgang, Hilgendorf, Inken, Hochhaus, Andrea, Andrieux, Geoffroy, Börries, Melanie, Busch, Hauke, Magenau, John, Reddy, Pavan, Labopin, Myriam, Antin, Joseph H, Henden, Andrea S, Hill, Geoffrey R, Kennedy, Glen A, Bar, Merav, Sarma, Anita, Mclornan, Donal, Mufti, Ghulam, Oran, Betul, Rezvani, Katayoun, Sha, Omid, Negrin, Robert S, Nagler, Arnon, Prinz, Marco, Burchert, Andrea, Neubauer, Andrea, Beelen, Dietrich, Mackensen, Andrea, von Bubnoff, Nikola, Herr, Wolfgang, Becher, Burkhard, Socié, Gerard, Caligiuri, Michael A, Ruggiero, Eliana, Bonini, Chiara, Häcker, Georg, Duyster, Justu, Finke, Jürgen, Pearce, Erika, Blazar, Bruce R, and Zeiser, Robert

Subjects
0301 basic medicine, Sorafenib, medicine.drug_class, Interferon Regulatory Factor-7, Medizin, Graft vs Host Disease, CD8-Positive T-Lymphocytes, Article, General Biochemistry, Genetics and Molecular Biology, Tyrosine-kinase inhibitor, Mice, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Animals, Humans, Transplantation, Homologous, Medicine, ddc:610, neoplasms, Interleukin-15, business.industry, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, General Medicine, Cellular Reprogramming, medicine.disease, Activating Transcription Factor 4, 3. Good health, Gene Expression Regulation, Neoplastic, Transplantation, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, fms-Like Tyrosine Kinase 3, Tandem Repeat Sequences, Interleukin 15, 030220 oncology & carcinogenesis, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Cancer research, IRF7, business, CD8, medicine.drug
Abstract

Contains fulltext : 190745.pdf (Publisher’s version ) (Closed access) Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Published
2018
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16. Outcomes of haploidentical stem cell transplantation for chronic lymphocytic leukemia: a retrospective study on behalf of the chronic malignancies working party of the EBMT

Author

Gwendolyn Van Gorkom, Patrice Chevallier, Nicolaus Kröger, Fabio Ciceri, Carol Moreno, Johannes Schetelig, Henric-Jan Blok, Paolo Corradini, Roberto Foa, Yener Koc, M. T. Van Lint, Dietrich W. Beelen, Didier Blaise, Johanna Tischer, Dominik Selleslag, Lutz P. Müller, Inken Hilgendorf, Joerg Thomas Bittenbring, Matthias Theobald, Dirk-Jan Eikema, Michel van Gelder, Michael Hallek, Carlos Solano, Luca Castagna, van Gorkom, Gwendolyn, van Gelder, Michel, Eikema, Dirk-Jan, Blok, Henric-Jan, van Lint, M. T., Koc, Yener, Ciceri, Fabio, Beelen, Dietrich, Chevallier, Patrice, Selleslag, Dominik, Blaise, Didier, Foá, Roberto, Corradini, Paolo, Castagna, Luca, Moreno, Carol, Solano, Carlo, Müller, Lutz Peter, Tischer, Johanna, Hilgendorf, Inken, Hallek, Michael, Bittenbring, Jörg, Theobald, Matthia, Schetelig, Johanne, Kröger, Nicolaus, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Interne Geneeskunde, and MUMC+: MA Hematologie (9)

Subjects
Oncology, Male, BLOOD, Chronic lymphocytic leukemia, medicine.medical_treatment, Medizin, MULTICENTER, Graft vs Host Disease, Hematopoietic stem cell transplantation, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Medicine, POSTTRANSPLANTATION CYCLOPHOSPHAMIDE, Cumulative incidence, ALLOGENEIC TRANSPLANTATION, DONOR TRANSPLANTATION, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, EUROPEAN-SOCIETY, surgical procedures, operative, Treatment Outcome, Transplantation, 030220 oncology & carcinogenesis, SURVIVAL, Female, medicine.drug, Adult, medicine.medical_specialty, Allogeneic transplantation, Cyclophosphamide, MINIMAL RESIDUAL DISEASE, 03 medical and health sciences, Internal medicine, Humans, Aged, Retrospective Studies, business.industry, Retrospective cohort study, medicine.disease, Minimal residual disease, BONE-MARROW-TRANSPLANTATION, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Analysis, Transplantation, Haploidentical, business, CLL, 030215 immunology
Abstract

Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post-transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT.

Published
2017

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