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101. Exagamglogene Autotemcel for Severe Sickle Cell Disease

Author

Frangoul, Haydar, Locatelli, Franco, Sharma, Akshay, Bhatia, Monica, Mapara, Markus, Molinari, Lyndsay, Wall, Donna, Liem, Robert I., Telfer, Paul, Shah, Ami J., Cavazzana, Marina, Corbacioglu, Selim, Rondelli, Damiano, Meisel, Roland, Dedeken, Laurence, Lobitz, Stephan, de Montalembert, Mariane, Steinberg, Martin H., Walters, Mark C., Bower, Laura, Imren, Suzan, Simard, Christopher, Xuan, Fengjuan, Zhou, Weiyu, Morrow, Phuong Khanh, Hobbs, William, and Grupp, Stephan

Published
2023
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102. Comparable Outcome after Busulfan- or Treosulfan-Based Conditioning Regimen in Children Above 4 Years of Age with ALL Undergoing Allogeneic HSCT. Results from the Prospective International Forum-Trial

Author

Kalwak, Krzysztof, Bader, Peter, Dalle, Jean-Hugues, Sedlacek, Petr, Buechner, Jochen, Ifversen, Marianne, Svec, Peter, Stein, Jerry, Güngör, Tayfun, Toporski, Jacek, Diaz De Heredia, Cristina, Bierings, Marc, Meisel, Roland, Ansari, Marc, Balduzzi, Adriana, Poetschger, Ulrike, Peters, Dr., and Locatelli, Franco

Published
2023
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104. Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations Correspondence Transplant International

Author

Lawitschka, Anita, Lucchini, Giovanna, Strahm, Brigitte, Dalle, Jean-Hugues, Gibson, Brenda, Balduzzi, Adriana, Diaz De Heredia, Cristina, Wachowiak, Jacek, Dalissier, Arnaud, Vettenranta, Kim, Yaniv, Isaac, Bordon, Victoria, Bauer, Dorothea, Bader, Peter, Meisel, Roland, Peters, Christina, Corbacioglu, Selim, Medizinische Universität Wien = Medical University of Vienna, Great Ormond Street Hospital for Children [London] (GOSH), University of Freiburg [Freiburg], Hôpital Robert Debré Paris, Hôpital Robert Debré, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Vall d'Hebron University Hospital [Barcelona], Poznan University of Medical Sciences [Poland] (PUMS), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Helsinki, Tel Aviv University [Tel Aviv], Ghent University Hospital, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], and Universität Regensburg (UR)

Subjects
acute GVHD, surgical procedures, operative, pediatrics, treatment, immune system diseases, hemic and lymphatic diseases, [SDV]Life Sciences [q-bio], hematopoietic cell transplantation, prophylaxis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

Published
2020
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105. Leitlinie : Empfehlungen der Fachgesellschaft zur Diagnostik und Therapie hämatologischer und onkologischer Erkrankungen

Author

Dreger, Peter, Strahm, Brigitte, Bornhäuser, Martin, Platzbecker, Uwe, Bader, Peter, Schmid, Christoph, Burchert, Andreas, Zeiser, Robert, Finke, Jürgen, Meisel, Roland, Bethge, Wolfgang Andreas, Christopeit, Maximilian Erich Joachim, Kobbe, Guido, Müller, Antonia Maria Susanne, Müller, Lutz Peter, Deutsche Arbeitsgemeinschaft Für Knochenmark- Und Blutstammzelltransplantation, Deutsche Gesellschaft Für Hämatologie Und Medizinische Onkologie, Beelen, Dietrich W., Sauer, Martin Günther, Einsele, Hermann, Kröger, Nicolaus, and Stelljes, Matthias

Subjects
Medizin und Gesundheit
Published
2020
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106. Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations

Author

Lawitschka, A, Lucchini, G, Strahm, B, Dalle, J, Balduzzi, A, Gibson, B, Diaz De Heredia, C, Wachowiak, J, Dalissier, A, Vettenranta, K, Yaniv, I, Bordon, V, Bauer, D, Bader, P, Meisel, R, Peters, C, Corbacioglu, S, Lawitschka, Anita, Lucchini, Giovanna, Strahm, Brigitte, Dalle, Jean-Hugues, Balduzzi, Adriana, Gibson, Brenda, Diaz De Heredia, Cristina, Wachowiak, Jacek, Dalissier, Arnaud, Vettenranta, Kim, Yaniv, Isaac, Bordon, Victoria, Bauer, Dorothea, Bader, Peter, Meisel, Roland, Peters, Christina, Corbacioglu, Selim, Lawitschka, A, Lucchini, G, Strahm, B, Dalle, J, Balduzzi, A, Gibson, B, Diaz De Heredia, C, Wachowiak, J, Dalissier, A, Vettenranta, K, Yaniv, I, Bordon, V, Bauer, D, Bader, P, Meisel, R, Peters, C, Corbacioglu, S, Lawitschka, Anita, Lucchini, Giovanna, Strahm, Brigitte, Dalle, Jean-Hugues, Balduzzi, Adriana, Gibson, Brenda, Diaz De Heredia, Cristina, Wachowiak, Jacek, Dalissier, Arnaud, Vettenranta, Kim, Yaniv, Isaac, Bordon, Victoria, Bauer, Dorothea, Bader, Peter, Meisel, Roland, Peters, Christina, and Corbacioglu, Selim

Abstract

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

Published
2020

107. Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency

Author

MS Infectieziekten, Infection & Immunity, Immuno/reuma patientenzorg, Child Health, Ghosh, Sujal, Köstel Bal, Sevgi, Edwards, Emily S J, Pillay, Bethany, Jimenez-Heredia, Raúl, Rao, Geetha, Erol Cipe, Funda, Salzer, Elisabeth, Zoghi, Samaneh, Abolhassani, Hassan, Momen, Tooba, Gostick, Emma, Price, David A, Zhang, Yu, Oler, Andrew J, Gonzaga-Jauregui, Claudia, Erman, Baran, Metin, Ayse, Ilhan, Inci, Haskologlu, Sule, Islamoglu, Candan, Baskin, Kubra, Ceylaner, Serdar, Yilmaz, Ebru, Unal, Ekrem, Karakukcu, Musa, Berghuis, Dagmar, Cole, Theresa, Gupta, Aditya Kumar, Hauck, Fabian, Hoepelman, Andy, Baris, Safa, Karakoc-Aydiner, Elif, Ozen, Ahmet, Kager, Leo, Holzinger, Dirk, Paulussen, Michael, Krüger, Renate, Meisel, Roland, Oommen, Prasad Thomas, Morris, Emma C, Neven, Benedicte, Worth, Austen J J, van Montfrans, Joris M, Fraaij, Pieter, Choo, Sharon, Dogu, Figen, Davies, E Graham, Burns, Siobhan, Dueckers, Gregor, Perez Becker, Ruy, von Bernuth, Horst, Latour, Sylvain, Faraci, Maura, Gattorno, Marco, Su, Helen, Pan-Hammarström, Qiang, Hammarström, Lennart, Lenardo, Michael J, Ma, Cindy S, Niehues, Tim, Aghamohammadi, Asghar, Rezaei, Nima, Ikinciogullari, Aydan, Tangye, Stuart G, Lankester, Arjan C, Boztug, Kaan, MS Infectieziekten, Infection & Immunity, Immuno/reuma patientenzorg, Child Health, Ghosh, Sujal, Köstel Bal, Sevgi, Edwards, Emily S J, Pillay, Bethany, Jimenez-Heredia, Raúl, Rao, Geetha, Erol Cipe, Funda, Salzer, Elisabeth, Zoghi, Samaneh, Abolhassani, Hassan, Momen, Tooba, Gostick, Emma, Price, David A, Zhang, Yu, Oler, Andrew J, Gonzaga-Jauregui, Claudia, Erman, Baran, Metin, Ayse, Ilhan, Inci, Haskologlu, Sule, Islamoglu, Candan, Baskin, Kubra, Ceylaner, Serdar, Yilmaz, Ebru, Unal, Ekrem, Karakukcu, Musa, Berghuis, Dagmar, Cole, Theresa, Gupta, Aditya Kumar, Hauck, Fabian, Hoepelman, Andy, Baris, Safa, Karakoc-Aydiner, Elif, Ozen, Ahmet, Kager, Leo, Holzinger, Dirk, Paulussen, Michael, Krüger, Renate, Meisel, Roland, Oommen, Prasad Thomas, Morris, Emma C, Neven, Benedicte, Worth, Austen J J, van Montfrans, Joris M, Fraaij, Pieter, Choo, Sharon, Dogu, Figen, Davies, E Graham, Burns, Siobhan, Dueckers, Gregor, Perez Becker, Ruy, von Bernuth, Horst, Latour, Sylvain, Faraci, Maura, Gattorno, Marco, Su, Helen, Pan-Hammarström, Qiang, Hammarström, Lennart, Lenardo, Michael J, Ma, Cindy S, Niehues, Tim, Aghamohammadi, Asghar, Rezaei, Nima, Ikinciogullari, Aydan, Tangye, Stuart G, Lankester, Arjan C, and Boztug, Kaan

Published
2020

109. Stem Cell Transplantation for Diamond–Blackfan Anemia. A Retrospective Study on Behalf of the Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT)

Author

Miano, Maurizio, primary, Eikema, Dirk-Jan, additional, de la Fuente, Josu, additional, Bosman, Paul, additional, Ghavamzadeh, Ardeshir, additional, Smiers, Frans, additional, Sengeløv, Henrik, additional, Yesilipek, Akif, additional, Formankova, Renata, additional, Bader, Peter, additional, Díaz Pérez, Miguel Ángel, additional, Bertrand, Yves, additional, Niemeyer, Charlotte, additional, Diallo, Safiatou, additional, Ansari, Marc, additional, Bykova, Tatiana A, additional, Faraci, Maura, additional, Bonanomi, Sonia, additional, Gozdzik, Jolanta, additional, Satti, Tariq Mahmood, additional, Bodova, Ivana, additional, Wölfl, Matthias, additional, Rocha, Vanderson G., additional, Mellgren, Karin, additional, Rascon, Jelena, additional, Holter, Wolfgang, additional, Lange, Andrzej, additional, Meisel, Roland, additional, Beguin, Yves, additional, Mozo, Yasmina, additional, Kriván, Gergely, additional, Sirvent, Anne, additional, Bruno, Benedicte, additional, Dalle, Jean Hugues, additional, Onofrillo, Daniela, additional, Giardino, Stefano, additional, Risitano, Antonio M., additional, de Latour, Régis Peffault, additional, and Dufour, Carlo, additional

Published
2021
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112. Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning

Author

Wustrau, Katharina, primary, Greil, Johann, additional, Sykora, Karl‐Walter, additional, Albert, Michael H., additional, Burkhardt, Birgit, additional, Lang, Peter, additional, Meisel, Roland, additional, Wössmann, Wilhelm, additional, Beier, Rita, additional, Schulz, Ansgar, additional, Bader, Peter, additional, Chada, Martin, additional, Kühl, Jörn‐Sven, additional, Schlegel, Paul‐Gerhardt, additional, Speckmann, Carsten, additional, Gruhn, Bernd, additional, Seidel, Markus, additional, Wawer, Angela, additional, Ozga, Ann‐Kathrin, additional, Janka, Gritta, additional, Ehl, Stephan, additional, Müller, Ingo, additional, and Lehmberg, Kai, additional

Published
2020
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113. Single Center Real Life Experiences in the Treatment of Pediatric, Adolescent and Young Adult ALL Patients Using Commercially Available CAR-T-Cells in Germany – Susceptibility to Bridging Chemotherapy Predicts Response.

Author

Bader, Peter, primary, Soerensen, Jan, additional, Rettinger, Eva, additional, Willasch, Andre, additional, Kalensee, Franziska, additional, Ansari, Marc, additional, Wolschke, Christine, additional, Noppeney, Richard, additional, Cario, Gunnar, additional, Kobbe, Guido, additional, Meisel, Roland, additional, Rossig, Claudia, additional, Klingebiel, Thomas E., additional, Schulz, Ansgar, additional, Hutter, Martin, additional, Ullrich, Evelyn, additional, Bönig, Halvard, additional, Huenecke, Sabine, additional, and Jarisch, Andrea, additional

Published
2020
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115. Additional file 1: of Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature

Author

Lucas-Sebastian Spitzhorn, Megges, Matthias, Wasco Wruck, Md Rahman, Jörg Otte, ÖZer Degistirici, Meisel, Roland, Rüdiger Sorg, Oreffo, Richard, and Adjaye, James

Abstract

Table S1. List of primary MSC samples. Table S2. List of primers. Table S3. List of antibodies. Figure S1 Pluripotency marker staining of generated iPSC line from fMSCs and aMSCs as well as EB formation. Figure S2. Correlation coeficiency table. Figure S3 Cytokine membranes. (DOCX 2493 kb)

Published
2019
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118. Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets

Author

Hoell, Jessica I, Ginzel, Sebastian, Kuhlen, Michaela, Kloetgen, Andreas, Gombert, Michael, Fischer, Ute, Hein, Daniel, Demir, Salih, Stanulla, Martin, Schrappe, Martin, Zur Stadt, Udo, Bader, Peter, Babor, Florian, Schuster, Friedhelm, Strahm, Brigitte, Alten, Julia, Moericke, Anja, Escherich, Gabriele, von Stackelberg, Arend, Thiele, Ralf, McHardy, Alice C, Peters, Christina, Bornhauser, Beat, Bourquin, Jean-Pierre, Krause, Stefan, Enczmann, Juergen, Meyer, Lüder Hinrich, Eckert, Cornelia, Borkhardt, Arndt, Meisel, Roland, Hoell, Jessica I, Ginzel, Sebastian, Kuhlen, Michaela, Kloetgen, Andreas, Gombert, Michael, Fischer, Ute, Hein, Daniel, Demir, Salih, Stanulla, Martin, Schrappe, Martin, Zur Stadt, Udo, Bader, Peter, Babor, Florian, Schuster, Friedhelm, Strahm, Brigitte, Alten, Julia, Moericke, Anja, Escherich, Gabriele, von Stackelberg, Arend, Thiele, Ralf, McHardy, Alice C, Peters, Christina, Bornhauser, Beat, Bourquin, Jean-Pierre, Krause, Stefan, Enczmann, Juergen, Meyer, Lüder Hinrich, Eckert, Cornelia, Borkhardt, Arndt, and Meisel, Roland

Abstract

Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.

Published
2019

119. Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche.

Author

Bennstein, Sabrina B., Weinhold, Sandra, Degistirici, Özer, Oostendorp, Robert A. J., Raba, Katharina, Kögler, Gesine, Meisel, Roland, Walter, Lutz, and Uhrberg, Markus

Subjects
STEM cell niches, HUMAN stem cells, MESENCHYMAL stem cells, INNATE lymphoid cells, CURRENT good manufacturing practices
Abstract

Innate lymphoid cells (ILCs) and in particular ILC3s have been described to be vital for mucosal barrier functions and homeostasis within the gastrointestinal (GI) tract. Importantly, IL-22-secreting ILC3 have been implicated in the control of inflammatory bowel disease (IBD) and were shown to reduce the incidence of graft-versus-host disease (GvHD) as well as the risk of transplant rejection. Unfortunately, IL-22-secreting ILC3 are primarily located in mucosal tissues and are not found within the circulation, making access to them in humans challenging. On this account, there is a growing desire for clinically applicable protocols for in vitro generation of effector ILC3. Here, we present an approach for faithful generation of functionally competent human ILC3s from cord blood-derived CD34+ hematopoietic progenitors on layers of human mesenchymal stem cells (MSCs) generated in good manufacturing practice (GMP) quality. The in vitro -generated ILC3s phenotypically, functionally, and transcriptionally resemble bona fide tissue ILC3 with high expression of the transcription factors (TF) RorγT, AHR, and ID2, as well as the surface receptors CD117, CD56, and NKp44. Importantly, the majority of ILC3 belonged to the desired effector subtype with high IL-22 and low IL-17 production. The protocol thus combines the advantages of avoiding xenogeneic components, which were necessary in previous protocols, with a high propensity for generation of IL-22-producing ILC3. The present approach is suitable for the generation of large amounts of ILC3 in an all-human system, which could facilitate development of clinical strategies for ILC3-based therapy in inflammatory diseases and cancer. [ABSTRACT FROM AUTHOR]

Published
2021
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121. 92 - Incidence of Secondary Malignancies after Total Body Irradiation-Based Allogeneic HSCT in Children with ALL – Long-Term Follow-up from the Prospective ALL-SCT 2003 Trial

Author

Eichinger, Anna, Glogova, Evgenia, Poetschger, Ulrike, Bader, Peter, Basu, Oliver, Beier, Rita, Burkhardt, Birgit, Classen, Carl-Friedrich, Claviez, Alexander, Corbacioglu, Selim, Deubzer, Hedwig, Greil, Johann, Gruhn, Bernd, Gungor, Tayfun, Kafa, Kinan, Lang, Peter, Lange, Bjoern Soenke, Mueller, Ingo, Sauer, Martin G., Schlegel, Paul-Gerhard, Schulz, Ansgar, Stachel, Klaus Daniel, Strahm, Brigitte R., Wawer, Angela, Kühl, Jörn-Sven, Meisel, Roland, Peters, Christina, and Albert, Michael H.

Published
2022
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122. Präklinische Untersuchung zum osteogenen Regenerationspotential von humanen und porkinen Mesenchymalen Stromazellen (MSCs) im Großtiermodell

Author

Grassmann, Jan, Degistirici, Özer, Grotheer, Vera, Tanner, Stephan, Meisel, Roland, Schneppendahl, Johannes, Windolf, Joachim, and Jungbluth, Pascal

Subjects
MSC, ddc: 610, Großtiermodell, Critical size defect, 610 Medical sciences, Medicine
Abstract

Fragestellung: Die Anwendung autologer Spongiosa zur Behandlung knöcherner Defekte ist als Goldstandard etabliert. Aufgrund der begrenzten Verfügbarkeit der Spongiosa und der verbundenen Entnahmemorbidität, sind Mesenchymale Stromazellen (MSCs) eine vielversprechende Alternative für[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2018)

Published
2018
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124. Risk factors for mixed chimerism after stem cell transplantation with treosulfan or melphalan based conditioning regimens in children and adolescents with primary hemophagocytic lymphohistocytosis

Author

Wustrau, Katharina, Albert, Michael H., Bader, Peter, Beier, Rita, Burkhardt, Birgit, Chada, Martin, Greil, Johann, Gruhn, Bernd, Kühl, Jörn-Sven, Lang, Peter, Meisel, Roland, Schulz, Ansgar, Seidel, Markus, Sykora, Karl-Walter, Wawer, Angela, Wössmann, Wilhelm, Ozga, Ann-Kathrin, Ehl, Stephan, Müller, Ingo, and Lehmberg, Kai

Subjects
Medizin
Published
2018

126. Correction: Hematopoietic stem cell transplantation for children with acute myeloid leukemia—results of the AML SCT-BFM 2007 trial

Author

Sauer, Martin G., primary, Lang, Peter J., additional, Albert, Michael H., additional, Bader, Peter, additional, Creutzig, Ursula, additional, Eyrich, Matthias, additional, Greil, Johann, additional, Gruhn, Bernd, additional, Holter, Wolfgang, additional, Klingebiel, Thomas, additional, Kremens, Bernhard, additional, von der Leyen, Heiko, additional, Mauz-Körholz, Christine, additional, Meisel, Roland, additional, Mischke, Kirsten, additional, Müller, Ingo, additional, Niemeyer, Charlotte M., additional, Peters, Christina, additional, Pohler, Christine, additional, Reinhardt, Dirk, additional, Burkhardt, Birgit, additional, Schlegel, Paul G., additional, Schulz, Ansgar S., additional, Schrum, Johanna, additional, Sedlacek, Petr, additional, Strahm, Brigitte, additional, Woessmann, Wilhelm, additional, Handgretinger, Rupert, additional, Zimmermann, Martin, additional, and Borkhardt, Arndt, additional

Published
2019
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127. Stem Cell Transplantation for Diamond-Blackfan Anemia. a Retrospective Study on Behalf of Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT)

Author

Miano, Maurizio, primary, Eikema, Dirk-Jan, primary, de la Fuente, Josu, primary, Bosman, Paul, primary, Ghavamzadeh, Ardeshir, primary, Smiers, Frans, primary, Sengeløv, Henrik, primary, Yesilipek, Akif, primary, Formankova, Renata, primary, Bader, Peter, primary, Díaz Pérez, Miguel Ángel, primary, Bertrand, Yves, primary, Niemeyer, Charlotte, primary, Bron, Dominique, primary, Ansari, Marc, primary, Bykova, Tatiana A, primary, Lanino, Edoardo, primary, Rovelli, Attilio, primary, Gozdzik, Jolanta, primary, Satti, Tariq Mahmood, primary, Bodova, Ivana, primary, Wölfl, Matthias, primary, Rocha, Vanderson G., primary, Mellgren, Karin, primary, Rascon, Jelena, primary, Lange, Andrzej, primary, Meisel, Roland, primary, Beguin, Yves, primary, Mozo, Yasmina, primary, Kriván, Gergely, primary, Sirvent, Anne, primary, Bruno, Benedicte, primary, Onofrillo, Daniela, primary, Risitano, Antonio M., primary, Peffault de Latour, Régis, primary, and Dufour, Carlo, primary

Published
2019
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128. Hematopoietic stem cell transplantation for children with acute myeloid leukemia—results of the AML SCT-BFM 2007 trial

Author

Sauer, Martin G., primary, Lang, Peter J., additional, Albert, Michael H., additional, Bader, Peter, additional, Creutzig, Ursula, additional, Eyrich, Matthias, additional, Greil, Johann, additional, Gruhn, Bernd, additional, Holter, Wolfgang, additional, Klingebiel, Thomas, additional, Kremens, Bernhard, additional, von der Leyen, Heiko, additional, Mauz-Körholz, Christine, additional, Meisel, Roland, additional, Mischke, Kirsten, additional, Müller, Ingo, additional, Niemeyer, Charlotte M., additional, Peters, Christina, additional, Pohler, Christine, additional, Reinhardt, Dirk, additional, Burkhardt, Birgit, additional, Schlegel, Paul G., additional, Schulz, Ansgar S., additional, Schrum, Johanna, additional, Sedlacek, Petr, additional, Strahm, Brigitte, additional, Woessmann, Wilhelm, additional, Handgretinger, Rupert, additional, Zimmermann, Martin, additional, and Borkhardt, Arndt, additional

Published
2019
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130. Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial

Author

Kuhlen, M, Willasch, A, Dalle, J, Wachowiak, J, Yaniv, I, Ifversen, M, Sedlacek, P, Guengoer, T, Lang, P, Bader, P, Sufliarska, S, Balduzzi, A, Strahm, B, von Luettichau, I, Hoell, J, Borkhardt, A, Klingebiel, T, Schrappe, M, von Stackelberg, A, Glogova, E, Poetschger, U, Meisel, R, Peters, C, Kuhlen, Michaela, Willasch, Andre M., Dalle, Jean-Hugues, Wachowiak, Jacek, Yaniv, Isaac, Ifversen, Marianne, Sedlacek, Petr, Guengoer, Tayfun, Lang, Peter, Bader, Peter, Sufliarska, Sabina, Balduzzi, Adriana, Strahm, Brigitte, von Luettichau, Irene, Hoell, Jessica I., Borkhardt, Arndt, Klingebiel, Thomas, Schrappe, Martin, von Stackelberg, Arend, Glogova, Evgenia, Poetschger, Ulrike, Meisel, Roland, Peters, Christina, Kuhlen, M, Willasch, A, Dalle, J, Wachowiak, J, Yaniv, I, Ifversen, M, Sedlacek, P, Guengoer, T, Lang, P, Bader, P, Sufliarska, S, Balduzzi, A, Strahm, B, von Luettichau, I, Hoell, J, Borkhardt, A, Klingebiel, T, Schrappe, M, von Stackelberg, A, Glogova, E, Poetschger, U, Meisel, R, Peters, C, Kuhlen, Michaela, Willasch, Andre M., Dalle, Jean-Hugues, Wachowiak, Jacek, Yaniv, Isaac, Ifversen, Marianne, Sedlacek, Petr, Guengoer, Tayfun, Lang, Peter, Bader, Peter, Sufliarska, Sabina, Balduzzi, Adriana, Strahm, Brigitte, von Luettichau, Irene, Hoell, Jessica I., Borkhardt, Arndt, Klingebiel, Thomas, Schrappe, Martin, von Stackelberg, Arend, Glogova, Evgenia, Poetschger, Ulrike, Meisel, Roland, and Peters, Christina

Abstract

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse.

Published
2018

131. Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome

Author

Gössling, Katharina L., Schipp, Cyrill, Fischer, Ute, Babor, Florian, Koch, Gerhard, Schuster, Friedhelm R., Dietzel-Dahmen, Jutta, Wieczorek, Dagmar, Borkhardt, Arndt, Meisel, Roland, and Kuhlen, Michaela

Subjects
agammaglobulinemia, ICF syndrome, Immunology, hematopoietic stem cell transplantation, facial anomaly, centromeric instability, immunodeficiency, Pneumocystis jirovecii pneumonia
Abstract

Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency, which leads to lethal infections if not recognized and treated in early childhood. Up-to-date treatment regimens consist of prophylactic and supportive treatment of the recurrent infections. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. He was initially admitted to the hospital with recurrent pulmonary infections from the opportunistic pathogen Pneumocystis jirovecii (PJ). Further immunological workup revealed agammaglobulinemia in the presence of B cells. After successful recovery from the PJ pneumonia, he underwent hematopoietic stem cell transplantation (HSCT) from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen consisting of treosulfan, fludarabine, and thiotepa. Other than acute chemotherapy-associated side effects, no serious adverse events occurred. Six months after HSCT immune-reconstitution, he had a stable chimerism with 2.9% autologous portion in the peripheral blood and a normal differential blood cell count, including all immunoglobulin subtypes. This is one of the first cases of successful HSCT in ICF syndrome. Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency. Centromeric instability and facial anomaly remain unaffected. Although the long-term patient outcome and the neurological development remain to be seen, this curative therapy for immunodeficiency improves life expectancy and quality of life. This case is meant to raise physicians awareness for ICF syndrome and highlight the consideration for HSCT in ICF syndrome early on.

Published
2017
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133. Results of a Prospective, Multicenter, Phase I/II Clinical Study in Pediatric and Adult Patients Using TCR Alpha/Beta and CD19 Depleted Haploidentical Hematopoietic Stem Cell Grafts Following Reduced-Intensity Conditioning

Author

Lang, Peter, primary, Handgretinger, Rupert, additional, Meisel, Roland, additional, Mielke, Stephan, additional, Niederwieser, Dietger, additional, Schlegel, Paul G., additional, Greil, Johann, additional, Schulz, Ansgar, additional, Bader, Peter, additional, Brecht, Arne, additional, Bunjes, Donald, additional, Kuball, Jurgen, additional, Schumm, Michael, additional, Eyrich, Matthias K., additional, Vucinic, Vladan, additional, Wiesneth, Markus, additional, Bonig, Halvard, additional, Westinga, Kasper, additional, Karitzky, Sandra, additional, Holtkamp, Silke, additional, Malchow, Michaela, additional, Siewert, Christiane, additional, Biedermann, Stefanie, additional, and Bethge, Wolfgang, additional

Published
2018
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134. Clearance of Treatment Refractory Adenoviremia via Adenovirus-specific Donor T-Cell Transfer During Aplasia After αβTCR-CD19–Depleted Stem Cell Transplantation

Author

Gössling, Katharina L, primary, Fouz, Hiba, additional, Kyrillopoulou, Olga, additional, Aubin, Matthias, additional, Maecker-Kolhoff, Britta, additional, Adams, Ortwin, additional, Borkhardt, Arndt, additional, Babor, Florian, additional, Schuster, Friedhelm R, additional, Siepermann, Meinolf, additional, Schumm, Michael, additional, Lang, Peter, additional, Eiz-Vesper, Britta, additional, and Meisel, Roland, additional

Published
2018
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135. Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial

Author

Kuhlen, Michaela, primary, Bader, Peter, additional, Sauer, Martin, additional, Albert, Michael H., additional, Gruhn, Bernd, additional, Güngör, Tayfun, additional, Kropshofer, Gabriele, additional, Lang, Peter, additional, Lawitschka, Anita, additional, Metzler, Markus, additional, Pentek, Falk, additional, Rossig, Claudia, additional, Schlegel, Paul G., additional, Schrappe, Martin, additional, Schrum, Johanna, additional, Schulz, Ansgar, additional, Schwinger, Wolfgang, additional, von Stackelberg, Arend, additional, Strahm, Brigitte, additional, Suttorp, Meinolf, additional, Luettichau, Irene Teichert-von, additional, Wößmann, Wilhelm, additional, Borkhardt, Arndt, additional, Meisel, Roland, additional, Poetschger, Ulrike, additional, Glogova, Evgenia, additional, and Peters, Christina, additional

Published
2018
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136. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders

Author

Slack, James, primary, Albert, Michael H., additional, Balashov, Dmitry, additional, Belohradsky, Bernd H., additional, Bertaina, Alice, additional, Bleesing, Jack, additional, Booth, Claire, additional, Buechner, Jochen, additional, Buckley, Rebecca H., additional, Ouachée-Chardin, Marie, additional, Deripapa, Elena, additional, Drabko, Katarzyna, additional, Eapen, Mary, additional, Feuchtinger, Tobias, additional, Finocchi, Andrea, additional, Gaspar, H. Bobby, additional, Ghosh, Sujal, additional, Gillio, Alfred, additional, Gonzalez-Granado, Luis I., additional, Grunebaum, Eyal, additional, Güngör, Tayfun, additional, Heilmann, Carsten, additional, Helminen, Merja, additional, Higuchi, Kohei, additional, Imai, Kohsuke, additional, Kalwak, Krzysztof, additional, Kanazawa, Nubuo, additional, Karasu, Gülsün, additional, Kucuk, Zeynep Y., additional, Laberko, Alexandra, additional, Lange, Andrzej, additional, Mahlaoui, Nizar, additional, Meisel, Roland, additional, Moshous, D., additional, Muramatsu, Hideki, additional, Parikh, Suhag, additional, Pasic, Srdjan, additional, Schmid, Irene, additional, Schuetz, Catharina, additional, Schulz, Ansgar, additional, Schultz, Kirk R., additional, Shaw, Peter J., additional, Slatter, Mary A., additional, Sykora, Karl-Walter, additional, Tamura, Shinobu, additional, Taskinen, Mervi, additional, Wawer, Angela, additional, Wolska-Kuśnierz, Beata, additional, Cowan, Morton J., additional, Fischer, Alain, additional, and Gennery, Andrew R., additional

Published
2018
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137. Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I‐BFM Study Group.

Author

Pichler, Herbert, Sedlacek, Petr, Meisel, Roland, Beier, Rita, Faraci, Maura, Kalwak, Krzysztof, Ifversen, Marianne, Müller, Ingo, Stein, Jerry, Vettenranta, Kim, Kropshofer, Gabriele, Kolenova, Alexandra, Karlhuber, Susanne, Glogova, Evgenia, Poetschger, Ulrike, Peters, Christina, Suttorp, Meinolf, Matthes‐Leodolter, Susanne, and Balduzzi, Adriana

Subjects
*HEMATOPOIETIC stem cell transplantation, *CHRONIC myeloid leukemia, *TEENAGERS, *PROTEIN-tyrosine kinase inhibitors, *GRAFT versus host disease
Abstract

Summary: This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan‐based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty‐two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first‐ or second‐generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1‐guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second‐year post‐transplant. All patients engrafted. The 1‐year transplant‐related mortality was 3% (confidence interval [CI]: 0%–6%). After a median follow‐up of 6.3 years, 5‐year overall survival and event‐free survival are 97% (CI: 93%–100%) and 91% (CI: 79%–100%) respectively. The current 5‐year leukaemia‐free survival with BCR::ABL1 <0.01% is 97% (CI: 88%–100%) and the current TKI‐ and DLI‐free survival is 95% (CI: 85%–100%). The incidence of chronic graft‐versus‐host disease (GvHD) was 32%, being severe in four patients (13%). At last follow‐up, 31 patients are GvHD‐free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP‐CML with an excellent disease‐free and TKI‐free survival. [ABSTRACT FROM AUTHOR]

Published
2024
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139. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Frismantas, Viktoras, Dobay, Maria Pamela, Rinaldi, Anna, Tchinda, Joelle, Dunn, Samuel H., Kunz, Joachim, Richter-Pechanska, Paulina, Marovca, Blerim, Pail, Orrin, Jenni, Silvia, Diaz-Flores, Ernesto, Chang, Bill H., Brown, Timothy J., Collins, Robert H., Uhrig, Sebastian, Balasubramanian, Gnana P., Bandapalli, Obul R., Higi, Salome, Eugster, Sabrina, Voegeli, Pamela, Delorenzi, Mauro, Cario, Gunnar, Loh, Mignon L., Schrappe, Martin, Stanulla, Martin, Kulozik, Andreas E., Muckenthaler, Martina U., Saha, Vaskar, Irving, Julie A., Meisel, Roland, Radimerski, Thomas, Von Stackelberg, Arend, Eckert, Cornelia, Tyner, Jeffrey W., Horvath, Peter, Bornhauser, Beat C., Bourquin, Jean-Pierre, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Frismantas, Viktoras, Dobay, Maria Pamela, Rinaldi, Anna, Tchinda, Joelle, Dunn, Samuel H., Kunz, Joachim, Richter-Pechanska, Paulina, Marovca, Blerim, Pail, Orrin, Jenni, Silvia, Diaz-Flores, Ernesto, Chang, Bill H., Brown, Timothy J., Collins, Robert H., Uhrig, Sebastian, Balasubramanian, Gnana P., Bandapalli, Obul R., Higi, Salome, Eugster, Sabrina, Voegeli, Pamela, Delorenzi, Mauro, Cario, Gunnar, Loh, Mignon L., Schrappe, Martin, Stanulla, Martin, Kulozik, Andreas E., Muckenthaler, Martina U., Saha, Vaskar, Irving, Julie A., Meisel, Roland, Radimerski, Thomas, Von Stackelberg, Arend, Eckert, Cornelia, Tyner, Jeffrey W., Horvath, Peter, Bornhauser, Beat C., and Bourquin, Jean-Pierre

Abstract

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.

Published
2017

140. Impact of human mesenchymal stromal cells on antifungal host response against Aspergillus fumigatus

Author

Schmidt, Stanislaw, Tramsen, Lars, Schneider, Andreas, Schubert, Ralf, Balan, Ada, Degistirici, Özer, Meisel, Roland, Lehrnbecher, Thomas, Schmidt, Stanislaw, Tramsen, Lars, Schneider, Andreas, Schubert, Ralf, Balan, Ada, Degistirici, Özer, Meisel, Roland, and Lehrnbecher, Thomas

Abstract

Mesenchymal stromal cells (MSCs) are increasingly given as immunotherapy to hematopoietic stem cell transplant (HSCT) recipients with refractory graft-versus-host disease (GvHD). Whereas the immunosuppressive properties of MSCs seem to be beneficial in GvHD, there is, at the same time, major concern that MSCs increase the risk for infection. We therefore investigated the interplay of human MSCs with Aspergillus fumigatus and the impact of MSCs on different arms of the anti-Aspergillus host response in vitro. Although A. fumigatus hyphae increase mRNA levels of IL6 in MSCs, the extracellular availability of IL-6 and other pro-inflammatory cytokines remains unaffected. Human MSCs are able to phagocyte Aspergillus conidia, but phagocytosis of conidia is not associated with an alteration of the cytokine production by MSCs. In addition, human MSCs do not affect activation and function of A. fumigatus specific CD4+ T cells, and MSCs do not negatively impact the oxidative burst activity of phagocytes. Our in vitro data indicate that administration of human MSCs is not associated with a negative impact on the host response against A. fumigatus and that the fungus does not stimulate MSCs to increase the release of those cytokines which play a central role in the pathophysiology of GvHD.

Published
2017

142. Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial

Author

Kuhlen, Michaela, primary, Willasch, Andre M., additional, Dalle, Jean-Hugues, additional, Wachowiak, Jacek, additional, Yaniv, Isaac, additional, Ifversen, Marianne, additional, Sedlacek, Petr, additional, Guengoer, Tayfun, additional, Lang, Peter, additional, Bader, Peter, additional, Sufliarska, Sabina, additional, Balduzzi, Adriana, additional, Strahm, Brigitte, additional, von Luettichau, Irene, additional, Hoell, Jessica I., additional, Borkhardt, Arndt, additional, Klingebiel, Thomas, additional, Schrappe, Martin, additional, von Stackelberg, Arend, additional, Glogova, Evgenia, additional, Poetschger, Ulrike, additional, Meisel, Roland, additional, and Peters, Christina, additional

Published
2017
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145. Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells

Author

Melcher, Marlen, primary, Danhauser, Katharina, additional, Seibt, Annette, additional, Degistirici, Özer, additional, Baertling, Fabian, additional, Kondadi, Arun Kumar, additional, Reichert, Andreas S., additional, Koopman, Werner J. H., additional, Willems, Peter H. G. M., additional, Rodenburg, Richard J., additional, Mayatepek, Ertan, additional, Meisel, Roland, additional, and Distelmaier, Felix, additional

Published
2017
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146. Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency

Author

Ghosh, Sujal, Köstel Bal, Sevgi, Edwards, Emily S. J., Pillay, Bethany, Jiménez Heredia, Raúl, Erol Cipe, Funda, Rao, Geetha, Salzer, Elisabeth, Zoghi, Samaneh, Abolhassani, Hassan, Momen, Tooba, Gostick, Emma, Price, David A., Zhang, Yu, Oler, Andrew J., Gonzaga-Jauregui, Claudia, Erman, Baran, Metin, Ayse, Ilhan, Inci, Haskologlu, Sule, Islamoglu, Candan, Baskin, Kubra, Ceylaner, Serdar, Yilmaz, Ebru, Unal, Ekrem, Karakukcu, Musa, Berghuis, Dagmar, Cole, Theresa, Gupta, Aditya K., Hauck, Fabian, Kogler, Hubert, Hoepelman, Andy I. M., Baris, Safa, Karakoc-Aydiner, Elif, Ozen, Ahmet, Kager, Leo, Holzinger, Dirk, Paulussen, Michael, Krüger, Renate, Meisel, Roland, Oommen, Prasad T., Morris, Emma, Neven, Benedicte, Worth, Austen, van Montfrans, Joris, Fraaij, Pieter L. A., Choo, Sharon, Dogu, Figen, Davies, E. Graham, Burns, Siobhan, Dückers, Gregor, Becker, Ruy Perez, von Bernuth, Horst, Latour, Sylvain, Faraci, Maura, Gattorno, Marco, Su, Helen C., Pan-Hammarström, Qiang, Hammarström, Lennart, Lenardo, Michael J., Ma, Cindy S., Niehues, Tim, Aghamohammadi, Asghar, Rezaei, Nima, Ikinciogullari, Aydan, Tangye, Stuart G., Lankester, Arjan C., and Boztug, Kaan

Abstract

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

Published
2020
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147. CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia

Author

Schmoellerl, Johannes, Barbosa, Inês Amorim Monteiro, Eder, Thomas, Brandstoetter, Tania, Schmidt, Luisa, Maurer, Barbara, Troester, Selina, Pham, Ha Thi Thanh, Sagarajit, Mohanty, Ebner, Jessica, Manhart, Gabriele, Aslan, Ezgi, Terlecki-Zaniewicz, Stefan, Van der Veen, Christa, Hoermann, Gregor, Duployez, Nicolas, Petit, Arnaud, Lapillonne, Helene, Puissant, Alexandre, Itzykson, Raphael, Moriggl, Richard, Heuser, Michael, Meisel, Roland, Valent, Peter, Sexl, Veronika, Zuber, Johannes, and Grebien, Florian

Abstract

Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion–dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion–driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.

Published
2020
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148. CDK6is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia

Author

Schmoellerl, Johannes, Barbosa, Inês Amorim Monteiro, Eder, Thomas, Brandstoetter, Tania, Schmidt, Luisa, Maurer, Barbara, Troester, Selina, Pham, Ha Thi Thanh, Sagarajit, Mohanty, Ebner, Jessica, Manhart, Gabriele, Aslan, Ezgi, Terlecki-Zaniewicz, Stefan, Van der Veen, Christa, Hoermann, Gregor, Duployez, Nicolas, Petit, Arnaud, Lapillonne, Helene, Puissant, Alexandre, Itzykson, Raphael, Moriggl, Richard, Heuser, Michael, Meisel, Roland, Valent, Peter, Sexl, Veronika, Zuber, Johannes, and Grebien, Florian

Abstract

Fusion proteins involving Nucleoporin 98(NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion–dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion–driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.

Published
2020
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149. Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Author

Nava, Tiago, Ansari, Marc, Dalle, Jean-Hugues, de Heredia, Christina Diaz, Güngör, Tayfun, Trigoso, Eugenia, Falkenberg, Ulrike, Bertaina, Alice, Gibson, Brenda, Jarisch, Andrea, Balduzzi, Adriana, Boenig, Halvard, Krivan, Gergely, Vettenranta, Kim, Matic, Toni, Buechner, Jochen, Kalwak, Krzysztof, Lawitschka, Anita, Yesilipek, Akif, Lucchini, Giovanna, Peters, Christina, Turkiewicz, Dominik, Niinimäki, Riitta, Diesch, Tamara, Lehrnbecher, Thomas, Sedlacek, Petr, Hutt, Daphna, Dalissier, Arnaud, Wachowiak, Jacek, Yaniv, Isaac, Stein, Jerry, Yalçin, Koray, Sisinni, Luisa, Deiana, Marco, Ifversen, Marianne, Kuhlen, Michaela, Meisel, Roland, Bakhtiar, Shahrzad, Cesaro, Simone, Willasch, Andre, Corbacioglu, Selim, and Bader, Peter

Abstract

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

Published
2020
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150. Hematopoietic stem cell transplantation for children with acute myeloid leukemia—results of the AML SCT-BFM 2007 trial

Author

Sauer, Martin G., Lang, Peter J., Albert, Michael H., Bader, Peter, Creutzig, Ursula, Eyrich, Matthias, Greil, Johann, Gruhn, Bernd, Holter, Wolfgang, Klingebiel, Thomas, Kremens, Bernhard, von der Leyen, Heiko, Mauz-Körholz, Christine, Meisel, Roland, Mischke, Kirsten, Müller, Ingo, Niemeyer, Charlotte M., Peters, Christina, Pohler, Christine, Reinhardt, Dirk, Burkhardt, Birgit, Schlegel, Paul G., Schulz, Ansgar S., Schrum, Johanna, Sedlacek, Petr, Strahm, Brigitte, Woessmann, Wilhelm, Handgretinger, Rupert, Zimmermann, Martin, and Borkhardt, Arndt

Abstract

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).

Published
2020
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