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154. CEBPAmutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome

Author

Taube, Franziska, Georgi, Julia Annabell, Kramer, Michael, Stasik, Sebastian, Middeke, Jan Moritz, Röllig, Christoph, Krug, Utz, Krämer, Alwin, Scholl, Sebastian, Hochhaus, Andreas, Brümmendorf, Tim H., Naumann, Ralph, Petzold, Andreas, Mulet-Lazaro, Roger, Valk, Peter J.M., Steffen, Björn, Einsele, Hermann, Schaich, Markus, Burchert, Andreas, Neubauer, Andreas, Schäfer-Eckart, Kerstin, Schliemann, Christoph, Krause, Stefan W., Hänel, Mathias, Noppeney, Richard, Kaiser, Ulrich, Baldus, Claudia D., Kaufmann, Martin, Herold, Sylvia, Stölzel, Friedrich, Sockel, Katja, von Bonin, Malte, Müller-Tidow, Carsten, Platzbecker, Uwe, Berdel, Wolfgang E., Serve, Hubert, Ehninger, Gerhard, Bornhäuser, Martin, Schetelig, Johannes, and Thiede, Christian

Abstract

Biallelic mutations of the CEBPAgene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPAmutations were identified in 240 patients (5.1%): 131 CEBPAbiand 109 CEBPAsm(60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbior CEBPAsmbZIPshared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD(median age, 63 years, median WBC 13.1 × 109/L; P< .001). Co-mutations were similar in both groups: GATA2mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIPvs 6.7% CEBPAsmTAD; P< .001) or NPM1mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIPvs 38.3% CEBPAsmTAD; P< .001). CEBPAbiand CEBPAsmbZIP, but not CEBPAsmTADwere associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-infand CEBPAother(including CEBPAsmTADand non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-infshowed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

Published
2022
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155. RNA-Based Detection of Gene Fusions in Formalin-Fixed and Paraffin-Embedded Solid Cancer Samples

Author

Kirchner, Martina, primary, Neumann, Olaf, additional, Volckmar, Anna-Lena, additional, Stögbauer, Fabian, additional, Allgäuer, Michael, additional, Kazdal, Daniel, additional, Budczies, Jan, additional, Rempel, Eugen, additional, Brandt, Regine, additional, Talla, Suranand Babu, additional, von Winterfeld, Moritz, additional, Leichsenring, Jonas, additional, Bochtler, Tilmann, additional, Krämer, Alwin, additional, Springfeld, Christoph, additional, Schirmacher, Peter, additional, Penzel, Roland, additional, Endris, Volker, additional, and Stenzinger, Albrecht, additional

Published
2019
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156. Efficacy and Safety of Single-Agent Quizartinib, a Potent and Selective FLT3 Inhibitor (FLT3i), in Patients (pts) With FLT3-Internal Tandem Duplication (FLT3-ITD) – Mutated Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) Enrolled in the Global, Phase 3, Randomized Controlled QuANTUM-R Trial

Author

Jonas, Brian A., primary, Cortes, Jorge E., additional, Khaled, Samer K., additional, Martinelli, Giovanni, additional, Perl, Alexander E., additional, Ganguly, Siddhartha, additional, Russell, Nigel H., additional, Krämer, Alwin, additional, Dombret, Hervé, additional, Hogge, Donna, additional, Leung, Anskar Y.-H., additional, Mehta, Priyanka, additional, Montesinos, Pau, additional, Radsak, Markus P., additional, Sica, Simona, additional, Arunachalam, Meena, additional, Holmes, Melissa, additional, Kobayashi, Ken, additional, Namuyinga, Ruth, additional, Ge, Nanxiang, additional, Yver, Antoine, additional, Zhang, Yufen, additional, and Levis, Mark J., additional

Published
2019
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157. EZH2 mutations and impact on clinical outcome: an analysis in 1,604 patients with newly diagnosed acute myeloid leukemia

Author

Stasik, Sebastian, primary, Middeke, Jan M., additional, Kramer, Michael, additional, Röllig, Christoph, additional, Krämer, Alwin, additional, Scholl, Sebastian, additional, Hochhaus, Andreas, additional, Crysandt, Martina, additional, Brümmendorf, Tim H., additional, Naumann, Ralph, additional, Steffen, Björn, additional, Kunzmann, Volker, additional, Einsele, Hermann, additional, Schaich, Markus, additional, Burchert, Andreas, additional, Neubauer, Andreas, additional, Schäfer-Eckart, Kerstin, additional, Schliemann, Christoph, additional, Krause, Stefan, additional, Herbst, Regina, additional, Hänel, Mathias, additional, Frickhofen, Norbert, additional, Noppeney, Richard, additional, Kaiser, Ulrich, additional, Baldus, Claudia D., additional, Kaufmann, Martin, additional, Rácil, Zdenek, additional, Platzbecker, Uwe, additional, Berdel, Wolfgang E., additional, Mayer, Jiri, additional, Serve, Hubert, additional, Müller-Tidow, Carsten, additional, Ehninger, Gerhard, additional, Bornhäuser, Martin, additional, Schetelig, Johannes, additional, and Thiede, Christian, additional

Published
2019
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159. Comparative genetic profiling aids diagnosis and clinical decision making in challenging cases of CUP syndrome

Author

Bochtler, Tilmann, primary, Endris, Volker, additional, Leichsenring, Jonas, additional, Reiling, Anna, additional, Neumann, Olaf, additional, Volckmar, Anna‐Lena, additional, Kirchner, Martina, additional, Allgäuer, Michael, additional, Schirmacher, Peter, additional, Krämer, Alwin, additional, and Stenzinger, Albrecht, additional

Published
2019
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161. Integrated Clinico-Molecular Characterization Identifies RAS Activation and CDKN2A Deletion As Independent Adverse Prognostic Factors in Cancer of Unknown Primary

Author

Bochtler, Tilmann, primary, Reiling, Anna, additional, Endris, Volker, additional, Hielscher, Thomas, additional, Volckmar, Anna-Lena, additional, Neumann, Olaf, additional, Kirchner, Martina, additional, Budczies, Jan, additional, Heukamp, Lukas C., additional, Leichsenring, Jonas, additional, Allgäuer, Michael, additional, Kazdal, Daniel, additional, Löffler, Harald, additional, Weichert, Wilko, additional, Schirmacher, Peter, additional, Stenzinger, Albrecht, additional, and Krämer, Alwin, additional

Published
2019
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163. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial

Author

Platzbecker, Uwe, primary, Middeke, Jan Moritz, additional, Sockel, Katja, additional, Herbst, Regina, additional, Wolf, Dominik, additional, Baldus, Claudia D, additional, Oelschlägel, Uta, additional, Mütherig, Anke, additional, Fransecky, Lars, additional, Noppeney, Richard, additional, Bug, Gesine, additional, Götze, Katharina S, additional, Krämer, Alwin, additional, Bochtler, Tilmann, additional, Stelljes, Matthias, additional, Groth, Christoph, additional, Schubert, Antje, additional, Mende, Marika, additional, Stölzel, Friedrich, additional, Borkmann, Christine, additional, Kubasch, Anne Sophie, additional, von Bonin, Malte, additional, Serve, Hubert, additional, Hänel, Mathias, additional, Dührsen, Ulrich, additional, Schetelig, Johannes, additional, Röllig, Christoph, additional, Kramer, Michael, additional, Ehninger, Gerhard, additional, Bornhäuser, Martin, additional, and Thiede, Christian, additional

Published
2018
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164. EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Author

Stasik, Sebastian, primary, Middeke, Jan Moritz, additional, Kramer, Michael, additional, Rollig, Christoph, additional, Krämer, Alwin, additional, Scholl, Sebastian, additional, Hochhaus, Andreas, additional, Crysandt, Martina, additional, Brümmendorf, Tim H., additional, Naumann, Ralph, additional, Steffen, Björn, additional, Kunzmann, Volker, additional, Einsele, Hermann, additional, Schaich, Markus, additional, Burchert, Andreas, additional, Neubauer, Andreas, additional, Schäfer-Eckart, Kerstin, additional, Schliemann, Christoph, additional, Krause, Stefan W, additional, Herbst, Regina, additional, Hänel, Mathias, additional, Frickhofen, Norbert, additional, Noppeney, Richard, additional, Kaiser, Ulrich, additional, Baldus, Claudia D., additional, Kaufmann, Martin, additional, Racil, Zdenek, additional, Platzbecker, Uwe, additional, Berdel, Wolfgang E., additional, Mayer, Jiri, additional, Serve, Hubert, additional, Müller-Tidow, Carsten, additional, Ehninger, Gerhard, additional, Bornhäuser, Martin, additional, Schetelig, Johannes, additional, and Thiede, Christian, additional

Published
2018
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165. PPM1D Mutations Are Rare in De Novo and Therapy-Related Acute Myeloid Leukemia

Author

Kartal-Kaess, Mutlu, primary, Bochtler, Tilmann, additional, Kraft, Bianca, additional, Kirsch, Michael, additional, Maier, Bettina, additional, Stoelzel, Friedrich, additional, Mohr, Brigitte, additional, Kramer, Michael, additional, Rollig, Christoph, additional, Thiede, Christian, additional, Bornhäuser, Martin, additional, Ehninger, Gerhard, additional, Müller-Tidow, Carsten, additional, and Krämer, Alwin, additional

Published
2018
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166. A phase I trial investigating the Aurora B kinase inhibitor BI 811283 in combination with cytarabine in patients with acute myeloid leukaemia

Author

Döhner, Hartmut, primary, Müller‐Tidow, Carsten, additional, Lübbert, Michael, additional, Fiedler, Walter, additional, Krämer, Alwin, additional, Westermann, Jörg, additional, Bug, Gesine, additional, Schlenk, Richard F., additional, Krug, Utz, additional, Goeldner, Rainer‐Georg, additional, Hilbert, James, additional, Taube, Tillmann, additional, and Ottmann, Oliver G., additional

Published
2018
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167. JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia—Letter

Author

von Bonin, Malte, primary, Moll, Katharina, additional, Kramer, Michael, additional, Oelschlägel, Uta, additional, Wermke, Martin, additional, Röllig, Christoph, additional, Thiede, Christian, additional, Ehninger, Gerhard, additional, Krämer, Alwin, additional, Müller-Tidow, Carsten, additional, Mitroulis, Ioannis, additional, and Bornhäuser, Martin, additional

Published
2018
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168. Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma

Author

Bochtler, Tilmann, primary, Merz, Maximilian, additional, Hielscher, Thomas, additional, Granzow, Martin, additional, Hoffmann, Korbinian, additional, Krämer, Alwin, additional, Raab, Marc-Steffen, additional, Hillengass, Jens, additional, Seckinger, Anja, additional, Kimmich, Christoph, additional, Dittrich, Tobias, additional, Müller-Tidow, Carsten, additional, Hose, Dirk, additional, Goldschmidt, Hartmut, additional, Hegenbart, Ute, additional, Jauch, Anna, additional, and Schönland, Stefan O., additional

Published
2018
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170. Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design.

Author

Ross, Jeffrey S., Sokol, Ethan S., Moch, Holger, Mileshkin, Linda, Baciarello, Giulia, Losa, Ferran, Beringer, Andreas, Thomas, Marlene, Elvin, Julia A., Ngo, Nhu, Jin, Dexter X., and Krämer, Alwin

Subjects
BIOMARKERS, GENETIC mutation, DNA, SEQUENCE analysis, CANCER of unknown primary origin, RETROSPECTIVE studies, MANN Whitney U Test, MOLECULAR biology, GENOMICS, GENE expression profiling, DESCRIPTIVE statistics, DATA analysis software, IMMUNOTHERAPY
Abstract

Background: Carcinoma of unknown primary origin (CUP) accounts for 2%–5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. Materials and Methods: Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture‐based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death‐ligand 1 (PD‐L1) positivity were determined. Results: A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD‐L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%. Conclusions: Thirty‐two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD‐L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP‐informed treatment. Clinical trial identification number. NCT03498521 Implications for Practice: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death‐ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling‐informed treatment. This article focuses on the ability of comprehensive genomic profiling to identify potentially targetable genetic alterations in cancers of unknown primary, based on the inclusion criteria for the CUPISCO clinical trial and aiming for more effective therapeutic options for patients. [ABSTRACT FROM AUTHOR]

Published
2021
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171. Impact of PTPN11mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

Author

Stasik, Sebastian, Eckardt, Jan-Niklas, Kramer, Michael, Röllig, Christoph, Krämer, Alwin, Scholl, Sebastian, Hochhaus, Andreas, Crysandt, Martina, Brümmendorf, Tim H., Naumann, Ralph, Steffen, Björn, Kunzmann, Volker, Einsele, Hermann, Schaich, Markus, Burchert, Andreas, Neubauer, Andreas, Schäfer-Eckart, Kerstin, Schliemann, Christoph, Krause, Stefan, Herbst, Regina, Hänel, Mathias, Frickhofen, Norbert, Noppeney, Richard, Kaiser, Ulrich, Baldus, Claudia D., Kaufmann, Martin, Rácil, Zdenek, Platzbecker, Uwe, Berdel, Wolfgang E., Mayer, Jiri, Serve, Hubert, Müller-Tidow, Carsten, Ehninger, Gerhard, Bornhäuser, Martin, Schetelig, Johannes, Middeke, Jan M., and Thiede, Christian

Abstract

The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11mutations were associated with concomitant mutations in NPM1(63%), DNMT3A(37%), and NRAS(21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P< .001) and higher white blood cell counts (P= .007) compared with PTPN11wild-type patients. In a multivariable analysis, PTPN11mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P< .001), relapse-free survival (HR: 1.52; P= .013), and a lower rate of complete remission (odds ratio: 0.46; P= .008). Importantly, the deleterious effect of PTPN11mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11mutations (HR: 2.28; P< .001) but not found with dominant PTPN11mutations (HR: 1.07; P= .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur.

Published
2021
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172. Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial

Author

Röllig, Christoph, Serve, Hubert, Noppeney, Richard, Hanoun, Maher, Krug, Utz, Baldus, Claudia D., Brandts, Christian H., Kunzmann, Volker, Einsele, Hermann, Krämer, Alwin, Müller-Tidow, Carsten, Schäfer-Eckart, Kerstin, Neubauer, Andreas, Burchert, Andreas, Giagounidis, Aristoteles, Krause, Stefan W., Mackensen, Andreas, Aulitzky, Walter, Herbst, Regina, Hänel, Mathias, Frickhofen, Norbert, Kullmer, Johannes, Kaiser, Ulrich, Kiani, Alexander, Link, Hartmut, Geer, Thomas, Reichle, Albrecht, Junghanß, Christian, Repp, Roland, Meinhardt, Achim, Dürk, Heinz, Klut, Ina-Maria, Bornhäuser, Martin, Schaich, Markus, Parmentier, Stefani, Görner, Martin, Thiede, Christian, von Bonin, Malte, Platzbecker, Uwe, Schetelig, Johannes, Kramer, Michael, Berdel, Wolfgang E., and Ehninger, Gerhard

Abstract

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n= 134) or placebo (n= 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p= 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p= 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p= 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.

Published
2021
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174. Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Author

Ganguly, Siddhartha, Cortes, Jorge E., Krämer, Alwin, Levis, Mark J., Martinelli, Giovanni, Perl, Alexander E., Russell, Nigel H., Arunachalam, Meena, Santos, Cedric Dos, Gammon, Guy, Lesegretain, Arnaud, Mires, Derek E., Pham, Hoang, Wang, Yibin, and Khaled, Samer K.

Abstract

•Quizartinib enabled more patients to undergo hematopoietic stem cell transplantation (HSCT) versus chemotherapy.•Continuation of quizartinib after HSCT was tolerable, with no new safety signals.•Quizartinib before and after HSCT may confer clinical benefits in relapsed/refractory FLT3-ITD acute myelogenous leukemia.

Published
2024
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175. CD7 is expressed on a subset of normal CD34-positive myeloid precursors

Author

Kriegsmann, Katharina, primary, Löffler, Harald, additional, Eckstein, Volker, additional, Schulz, Renate, additional, Kräker, Sandra, additional, Braun, Ute, additional, Luft, Thomas, additional, Hegenbart, Ute, additional, Schönland, Stefan, additional, Dreger, Peter, additional, Krämer, Alwin, additional, Ho, Anthony D., additional, Müller-Tidow, Carsten, additional, and Hundemer, Michael, additional

Published
2018
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176. Phase I dose‐escalation trial investigating volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukaemia

Author

Ottmann, Oliver G., primary, Müller‐Tidow, Carsten, additional, Krämer, Alwin, additional, Schlenk, Richard F., additional, Lübbert, Michael, additional, Bug, Gesine, additional, Krug, Utz, additional, Bochtler, Tilmann, additional, Voss, Florian, additional, Taube, Tillmann, additional, Liu, Dan, additional, Garin‐Chesa, Pilar, additional, and Döhner, Hartmut, additional

Published
2018
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177. Integrated Histogenetic Analysis Reveals BAP1 -Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary

Author

Bochtler, Tilmann, primary, Endris, Volker, additional, Reiling, Anna, additional, Leichsenring, Jonas, additional, Schweiger, Michal R., additional, Klein, Sebastian, additional, Stögbauer, Fabian, additional, Goeppert, Benjamin, additional, Schirmacher, Peter, additional, Krämer, Alwin, additional, and Stenzinger, Albrecht, additional

Published
2018
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180. The Addition of Sorafenib to Standard AML Treatment Results in a Substantial Reduction in Relapse Risk and Improved Survival. Updated Results from Long-Term Follow-up of the Randomized-Controlled Soraml Trial

Author

Rollig, Christoph, primary, Serve, Hubert, additional, Hüttmann, Andreas, additional, Noppeney, Richard, additional, Müller-Tidow, Carsten, additional, Krug, Utz, additional, Baldus, Claudia D., additional, Brandts, Christian H., additional, Kunzmann, Volker, additional, Einsele, Hermann, additional, Krämer, Alwin, additional, Schäfer-Eckart, Kerstin, additional, Neubauer, Andreas, additional, Burchert, Andreas, additional, Giagounidis, Aristoteles, additional, Krause, Stefan W., additional, Mackensen, Andreas, additional, Aulitzky, Walter E., additional, Herbst, Regina, additional, Hänel, Mathias, additional, Kiani, Alexander, additional, Frickhofen, Norbert, additional, Kullmer, Johannes, additional, Kaiser, Ulrich, additional, Link, Hartmut, additional, Geer, Thomas, additional, Reichle, Albrecht, additional, Junghanss, Christian, additional, Repp, Roland, additional, Heits, Frank, additional, Durk, Heinz Albert, additional, Illmer, Thomas, additional, Bornhäuser, Martin, additional, Schaich, Markus, additional, Parmentier, Stefani Barbara, additional, Goerner, Martin, additional, Thiede, Christian, additional, von Bonin, Malte, additional, Schetelig, Johannes, additional, Kramer, Michael, additional, Berdel, Wolfgang E., additional, and Ehninger, Gerhard, additional

Published
2017
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181. Cep164-null cells generated by genome editing show a ciliation defect with intact dna repair capacity

Author

Daly, Owen M., Gaboriau, David, Karakaya, Kadin, King, Sinéad, Dantas, Tiago J., Lalor, Pierce, Dockery, Peter, Krämer, Alwin, and Morrison, Ciaran G.

Subjects
primary cilium formation, ciliopathy, centrosome, cep164, DNA repair, centriole, centrosome amplification, DNA damage response, protein, damage, localization, primary cilium, maintenance
Abstract

Primary cilia are microtubule structures that extend from the distal end of the mature, mother centriole. CEP164 is a component of the distal appendages carried by the mother centriole that is required for primary cilium formation. Recent data have implicated CEP164 as a ciliopathy gene and suggest that CEP164 plays some roles in the DNA damage response (DDR). We used reverse genetics to test the role of CEP164 in the DDR. We found that conditional depletion of CEP164 in chicken DT40 cells using an auxin-inducible degron led to no increase in sensitivity to DNA damage induced by ionising or ultraviolet irradiation. Disruption of CEP164 in human retinal pigmented epithelial cells blocked primary cilium formation but did not affect cellular proliferation or cellular responses to ionising or ultraviolet irradiation. Furthermore, we observed no localisation of CEP164 to the nucleus using immunofluorescence microscopy and analysis of multiple tagged forms of CEP164. Our data suggest that CEP164 is not required in the DDR.

Published
2016

182. Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Missegregation in Cancer

Author

Cosenza, Marco R., primary, Cazzola, Anna, additional, Rossberg, Annik, additional, Schieber, Nicole L., additional, Konotop, Gleb, additional, Bausch, Elena, additional, Slynko, Alla, additional, Holland-Letz, Tim, additional, Raab, Marc S., additional, Dubash, Taronish, additional, Glimm, Hanno, additional, Poppelreuther, Sven, additional, Herold-Mende, Christel, additional, Schwab, Yannick, additional, and Krämer, Alwin, additional

Published
2017
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187. Marker chromosomes can arise from chromothripsis and predict adverse prognosis in acute myeloid leukemia

Author

Bochtler, Tilmann, primary, Granzow, Martin, additional, Stölzel, Friedrich, additional, Kunz, Christina, additional, Mohr, Brigitte, additional, Kartal-Kaess, Mutlu, additional, Hinderhofer, Katrin, additional, Heilig, Christoph E., additional, Kramer, Michael, additional, Thiede, Christian, additional, Endris, Volker, additional, Kirchner, Martina, additional, Stenzinger, Albrecht, additional, Benner, Axel, additional, Bornhäuser, Martin, additional, Ehninger, Gerhard, additional, Ho, Anthony D., additional, Jauch, Anna, additional, and Krämer, Alwin, additional

Published
2017
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188. Marker Chromosomes Can Arise from Chromothripsis and Predict Adverse Prognosis in Acute Myeloid Leukemia

Author

Bochtler, Tilmann, primary, Granzow, Martin, additional, Stölzel, Friedrich, additional, Kunz, Christina, additional, Mohr, Brigitte, additional, Kartal-Kaess, Mutlu, additional, Janssen, Johannes W.G., additional, Heilig, Christoph E., additional, Kramer, Michael, additional, Thiede, Christian, additional, Benner, Axel, additional, Bornhäuser, Martin, additional, Ehninger, Gerhard, additional, Ho, Anthony D., additional, Jauch, Anna, additional, and Krämer, Alwin, additional

Published
2016
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189. Comparison of Treatment Strategies in Patients over 60 Years with AML: Final Analysis of a Prospective Randomized German AML Intergroup Study

Author

Niederwieser, Dietger, primary, Hoffmann, Verena Sophia, additional, Pfirrmann, Markus, additional, Al-Ali, Haifa Kathrin, additional, Schwind, Sebastian, additional, Vucinic, Vladan, additional, Krahl, Rainer, additional, Kahl, Christoph, additional, Wolf, Hans-Heinrich, additional, Kreibich, Ute, additional, Hähling, Detlef, additional, Hegenbart, Ute, additional, Hirt, Carsten, additional, Peter, Norma, additional, Florschuetz, Axel, additional, Reifenrath, Kolja, additional, Schulze, Antje, additional, Zojer, Niklas, additional, Scholl, Sebastian, additional, Junghanss, Christian, additional, Pönisch, Wolfram, additional, Heyn, Simone, additional, Sayer, Herbert G., additional, Hochhaus, Andreas, additional, Heinicke, Thomas, additional, Fischer, Thomas, additional, Krämer, Alwin, additional, Dreger, Peter, additional, Maschmeyer, Georg, additional, Krug, Utz, additional, Sauerland, Maria Christina, additional, Heinecke, Achim, additional, Hehlmann, Rüdiger, additional, Lengfelder, Eva, additional, Hiddemann, Wolfgang, additional, Serve, Hubert, additional, Müller-Tidow, Carsten, additional, Berdel, Wolfgang E, additional, and Büchner, Thomas, additional

Published
2016
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190. Allogeneic Stem Cell Transplantation Improves Survival in Patients with FLT3-ITD-Negative and NPM1-Wild Type Intermediate Risk (ELN) Acute Myeloid Leukemia

Author

Heidrich, Katharina, primary, Thiede, Christian, additional, Schäfer-Eckart, Kerstin, additional, Schmitz, Norbert, additional, Aulitzky, Walter E, additional, Krämer, Alwin, additional, Rösler, Wolf, additional, Hänel, Mathias, additional, Einsele, Hermann, additional, Baldus, Claudia D., additional, Trappe, Ralf U, additional, Stölzel, Friedrich, additional, Middeke, Jan Moritz, additional, Röllig, Christoph, additional, Kramer, Michael, additional, Serve, Hubert, additional, Berdel, Wolfgang E, additional, Ehninger, Gerhard, additional, Bornhäuser, Martin, additional, and Schetelig, Johannes, additional

Published
2016
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191. Clinical Impact of KMT2C and SPRY4 Expression Levels in Intensively Treated Younger Adult Acute Myeloid Leukemia Patients

Author

Kayser, Sabine, primary, Feszler, Maximilian, additional, Krzykalla, Julia, additional, Schick, Matthias, additional, Hielscher, Thomas, additional, Benner, Axel, additional, Kramer, Michael, additional, Thol, Felicitas, additional, Platzbecker, Uwe, additional, Ho, Anthony D., additional, Ehninger, Gerhard, additional, Heuser, Michael, additional, Thiede, Christian, additional, Röllig, Christoph, additional, and Krämer, Alwin, additional

Published
2016
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192. Expanded Phenotypic and Genetic Heterogeneity in the Clinical Spectrum of FPD-AML: Lymphoid Malignancies and Skin Disorders Are Common Features in Carriers of Germline RUNX1 Mutations

Author

Brown, Anna L, primary, Hahn, Christopher N, additional, Carmichael, Catherine, additional, Wilkins, Ella, additional, Babic, Milena, additional, Chong, Chan-Eng, additional, Li, Xiao-Chun, additional, Michaud, Joelle, additional, Cannon, Ping, additional, Poplawski, Nicola, additional, Altree, Meryl, additional, Phillips, Kerry, additional, Jaensch, Louise, additional, Fine, Miriam, additional, Schreiber, Andreas W, additional, Feng, Jinghua, additional, Rawlings, Lesley, additional, Vakulin, Cassandra, additional, Butcher, Carolyn, additional, D'Andrea, Richard, additional, Lewis, Ian D, additional, Patton, Nigel, additional, Forsyth, Cecily, additional, Mapp, Sally, additional, Mar Fan, Helen, additional, Susman, Rachel, additional, Morgan, Sue, additional, Cooney, Julian, additional, Currie, Mark S, additional, Popat, Uday R., additional, Bradstock, Kenneth, additional, Sorrell, April D., additional, Owen, Carolyn J., additional, Horwitz, Marshall S, additional, Hiwase, Devendra, additional, Krämer, Alwin, additional, Fröhling, Stefan, additional, Godley, Lucy A, additional, Churpek, Jane E, additional, and Scott, Hamish S, additional

Published
2016
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194. The clinical mutatome of core binding factor leukemia

Author

Opatz, Sabrina, Bamopoulos, Stefanos A., Metzeler, Klaus H., Herold, Tobias, Ksienzyk, Bianka, Bräundl, Kathrin, Tschuri, Sebastian, Vosberg, Sebastian, Konstandin, Nikola P., Wang, Christine, Hartmann, Luise, Graf, Alexander, Krebs, Stefan, Blum, Helmut, Schneider, Stephanie, Thiede, Christian, Middeke, Jan Moritz, Stölzel, Friedrich, Röllig, Christoph, Schetelig, Johannes, Ehninger, Gerhard, Krämer, Alwin, Braess, Jan, Görlich, Dennis, Sauerland, Maria Cristina, Berdel, Wolfgang E., Wörmann, Bernhard J., Hiddemann, Wolfgang, Spiekermann, Karsten, Bohlander, Stefan K., and Greif, Philipp A.

Abstract

The fusion genes CBFB/MYH11and RUNX1/RUNX1T1block differentiation through disruption of the core binding factor (CBF) complex and are found in 10–15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum (‘mutatome’) in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2,and ZBTB7Abeing strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A,and DHX15and identified novel, recurrent mutations in NFE2(3%), MN1(4%), HERC1(3%), and ZFHX4(5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.

Published
2020
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195. TP53deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia

Author

Cazzola, Anna, Schlegel, Christin, Jansen, Ilka, Bochtler, Tilmann, Jauch, Anna, and Krämer, Alwin

Abstract

Abnormal karyotypes are common in cancer cells and frequently observed in acute myeloid leukemia (AML), in which complex karyotype aberrations are associated with poor prognosis. How exactly abnormal karyotypes arise and are propagated in AML is unclear. TP53mutations and deletions are frequent in complex karyotype AML, suggesting a role of TP53alterations in the development of chromosome abnormalities. Here, we generated isogenic TP53-knockout versions of the euploid AML cell line EEB to investigate the impact of TP53on karyotype stability. We show that chromosome abnormalities spontaneously arise in TP53-deficient cells. Numerical aneuploidy could, to some extent, be propagated in a TP53-proficient setting, indicating that it does not necessarily trigger TP53 activation. In contrast, tolerance to structural chromosome aberrations was almost entirely restricted to TP53-knockout clones, all of which were able to continue proliferation in the presence of damaged DNA. Mechanistically, as a source of chromosome aberrations, limited numerical but not structural chromosomal instability was tolerated by TP53-wildtype cells. In contrast, structural instability was found only in TP53-knockout cells. Together, in myeloid cells TP53loss allows for the development of complex karyotype aberrations and karyotype heterogeneity by perpetuation of chromosome segregation errors.

Published
2019
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196. A phase I trial investigating the Aurora B kinase inhibitor BI 811283 in combination with cytarabine in patients with acute myeloid leukaemia.

Author

Döhner, Hartmut, Schlenk, Richard F., Taube, Tillmann, Müller‐Tidow, Carsten, Krug, Utz, Lübbert, Michael, Fiedler, Walter, Krämer, Alwin, Westermann, Jörg, Bug, Gesine, Ottmann, Oliver G., Goeldner, Rainer‐Georg, and Hilbert, James

Subjects
CYTARABINE, KINASE inhibitors, AURORA kinases
Abstract

The article discusses the efficiency and impact of the Aurora B kinase inhibitor BI 81128 along with the combination of the medication cytarabine on patients diagnosed with acute myeloid leukaemia (AML). It talks about the clinical trial conducted to understand the efficiency, safety and the pharmacokinetics (PK) of the inhibitor in the patients with AML.

Published
2019
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197. Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial.

Author

Bixby, Dale, Fiedler, Walter, Dimier, Natalie, Simmons, Brian P., Riehl, Todd, Colburn, Dawn, Noppeney, Richard, Lin, Tara L., Cortes, Jorge, Krauter, Jürgen, Yee, Karen, Medeiros, Bruno C., Krämer, Alwin, and Assouline, Sarit

Subjects
AZACITIDINE, ACUTE myeloid leukemia, VISMODEGIB
Abstract

The article focuses on the efficiency of the Hedgehog pathway inhibitor (HPI) Vismodegib in the treatment of patients experiencing a relapse of acute myeloid leukaemia (AML). It talks about the Hedgehog signalling being important in maintaining leukaemia stem cells (LSCs) in the patient's body. It tells about Vismodegib being able to bind Smoothened (SMO) in the body.

Published
2019
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198. Phase I dose‐escalation trial investigating volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukaemia.

Author

Ottmann, Oliver G., Müller‐Tidow, Carsten, Krämer, Alwin, Schlenk, Richard F., Lübbert, Michael, Bug, Gesine, Krug, Utz, Bochtler, Tilmann, Voss, Florian, Taube, Tillmann, Liu, Dan, Garin‐Chesa, Pilar, and Döhner, Hartmut

Subjects
CYTARABINE, MATHEMATICAL combinations
Abstract

The article presents the phase one results of a study on volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML). Topics discussed include dose escalations and dose-limiting toxicities, most common treatment-related adverse events (AEs,) and safety profile of volasertib in AML patients.

Published
2019
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200. Abstract 2645: BAY 1436032: A highly selective, potent and orally available inhibitor of mutant forms of IDH1

Author

Panknin, Olaf, primary, Pusch, Stefan, additional, Herbst, Lena, additional, Kaulfuss, Stefan, additional, Zimmermann, Katja, additional, Rehwinkel, Hartmut, additional, Neuhaus, Roland, additional, Ring, Sven, additional, Brüning, Michael, additional, Stark, Claudia, additional, Prelle, Katja, additional, Michels, Martin, additional, Jeffers, Michael, additional, Hess-Stumpp, Holger, additional, Ziegelbauer, Karl, additional, Brands, Michael, additional, Krämer, Alwin, additional, and von Deimling, Andreas, additional

Published
2016
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