20 results on '"Maria Cristina Sauerland"'
Search Results
2. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation
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Luise Hartmann, Sayantanee Dutta, Sabrina Opatz, Sebastian Vosberg, Katrin Reiter, Georg Leubolt, Klaus H. Metzeler, Tobias Herold, Stefanos A. Bamopoulos, Kathrin Bräundl, Evelyn Zellmeier, Bianka Ksienzyk, Nikola P. Konstandin, Stephanie Schneider, Karl-Peter Hopfner, Alexander Graf, Stefan Krebs, Helmut Blum, Jan Moritz Middeke, Friedrich Stölzel, Christian Thiede, Stephan Wolf, Stefan K. Bohlander, Caroline Preiss, Linping Chen-Wichmann, Christian Wichmann, Maria Cristina Sauerland, Thomas Büchner, Wolfgang E. Berdel, Bernhard J. Wörmann, Jan Braess, Wolfgang Hiddemann, Karsten Spiekermann, and Philipp A. Greif
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Science - Abstract
The t(8;21) translocation is often found in acute myeloid leukaemia but is not sufficient for development of the disease. In this study, the authors identify frequent mutations in the transcriptional repressor, ZBTB7A, in these patients and show that the mutations reduce DNA binding activity.
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- 2016
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3. A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia
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Tobias Herold, Vindi Jurinovic, Aarif M. N. Batcha, Stefanos A. Bamopoulos, Maja Rothenberg-Thurley, Bianka Ksienzyk, Luise Hartmann, Philipp A. Greif, Julia Phillippou-Massier, Stefan Krebs, Helmut Blum, Susanne Amler, Stephanie Schneider, Nikola Konstandin, Maria Cristina Sauerland, Dennis Görlich, Wolfgang E. Berdel, Bernhard J. Wörmann, Johanna Tischer, Marion Subklewe, Stefan K. Bohlander, Jan Braess, Wolfgang Hiddemann, Klaus H. Metzeler, Ulrich Mansmann, and Karsten Spiekermann
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Primary therapy resistance is a major problem in acute myeloid leukemia treatment. We set out to develop a powerful and robust predictor for therapy resistance for intensively treated adult patients. We used two large gene expression data sets (n=856) to develop a predictor of therapy resistance, which was validated in an independent cohort analyzed by RNA sequencing (n=250). In addition to gene expression markers, standard clinical and laboratory variables as well as the mutation status of 68 genes were considered during construction of the model. The final predictor (PS29MRC) consisted of 29 gene expression markers and a cytogenetic risk classification. A continuous predictor is calculated as a weighted linear sum of the individual variables. In addition, a cut off was defined to divide patients into a high-risk and a low-risk group for resistant disease. PS29MRC was highly significant in the validation set, both as a continuous score (OR=2.39, P=8.63·10−9, AUC=0.76) and as a dichotomous classifier (OR=8.03, P=4.29·10−9); accuracy was 77%. In multivariable models, only TP53 mutation, age and PS29MRC (continuous: OR=1.75, P=0.0011; dichotomous: OR=4.44, P=0.00021) were left as significant variables. PS29MRC dominated all models when compared with currently used predictors, and also predicted overall survival independently of established markers. When integrated into the European LeukemiaNet (ELN) 2017 genetic risk stratification, four groups (median survival of 8, 18, 41 months, and not reached) could be defined (P=4.01·10−10). PS29MRC will make it possible to design trials which stratify induction treatment according to the probability of response, and refines the ELN 2017 classification.
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- 2018
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- View/download PDF
4. RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes
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Philipp A. Greif, Nikola P. Konstandin, Klaus H. Metzeler, Tobias Herold, Zlatana Pasalic, Bianka Ksienzyk, Annika Dufour, Friederike Schneider, Stephanie Schneider, Purvi M. Kakadia, Jan Braess, Maria Cristina Sauerland, Wolfgang E. Berdel, Thomas Büchner, Bernhard J. Woermann, Wolfgang Hiddemann, Karsten Spiekermann, and Stefan K. Bohlander
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The RUNX1 (AML1) gene is a frequent mutational target in myelodysplastic syndromes and acute myeloid leukemia. Previous studies suggested that RUNX1 mutations may have pathological and prognostic implications.Design and Methods We screened 93 patients with cytogenetically normal acute myeloid leukemia for RUNX1 mutations by capillary sequencing of genomic DNA. Mutation status was then correlated with clinical data and gene expression profiles.Results We found that 15 out of 93 (16.1%) patients with cytogenetically normal acute myeloid leukemia had RUNX1 mutations. Seventy-three patients were enrolled in the AMLCG-99 trial and carried ten RUNX1 mutations (13.7%). Among these 73 patients RUNX1 mutations were significantly associated with older age, male sex, absence of NPM1 mutations and presence of MLL-partial tandem duplications. Moreover, RUNX1-mutated patients had a lower complete remission rate (30% versus 73% P=0.01), lower relapse-free survival rate (3-year relapse-free survival 0% versus 30.4%; P=0.002) and lower overall survival rate (3-year overall survival 0% versus 34.4%; P
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- 2012
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5. Acute Myeloid Leukemia (AML): The Role of Intensive Induction Chemotherapy
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Thomas Büchner, Wolfgang Hiddemann, Wolfgang E. Berdel, Bernhard Wörmann, Helmut Löffler, Claudia Schoch, Torsten Haferlach, Wolf-Dieter Ludwig, Georg Maschmeyer, Eva Lengelder, Peter Staib, Reinhard Andreesen, Leopold Balleisen, Detlef Haase, Hartmut Eimermacher, Andrea Schumacher, Carlo Aul, Herbert Rasche, Jens Uhlig, Andreas Grüneisen, Hans Edgar Reis, Joachim Hartlapp, Wolf-Dietrich Hirschmann, Hans-Josef Weh, Hermann-Josef Pielken, Winfried Gassmann, Maria-Cristina Sauerland, and Achim Heinecke for the German AML Cooperative Group
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double induction ,high-dose AraC ,daunorubicin dosage ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Intensive induction therapy-in acute myeloid leukemia (AML), as in some other systemic malignancies- is a strategy fundamentally different from post-remission strategies. Approaches like consolidation treatment, prolonged mainte¬nance, and autologous or allogeneic transplantation in the first remission are directed against minimal residual disease with a malignant cell population having survived the induction treatment. In contrast, induction therapy deals with naive tumor cells possibly different in their sensitivity from their counterparts in remission. Therefore, in AML it has been suggested to introduce intensification strategies into the induction part of treatment as a new step after the preceding intensification steps in the post-remission part. As expected from the dose effects observed in post-remission treatment using more AraC or longer treatment, similar dose effects have been found in the induction treatment both by the incorporation of high-dose AraC and by the double induction strategy administered in patients up to 60 years of age. For example, patients with poor risk AML due to an unfavorable karyotype, high LDH in serum, or delayed response, benefited from double induction containing high-dose AraC by a longer survival as compared to that from standard dose AraC. A corresponding dose effect in the induction treatment has been found in patients of 60 years and older receiving daunorubicin 60 vs 30 mg/m2 as part of the TAD regimen with higher dosage. This treatment significantly increased the response and survival rate in older patients who represented a poor risk group as a whole. Thus, we could demonstrate, both in younger and older patients, that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits a cumulative toxicity in that a repetition of courses containing high-dose AraC in the post-remission period is associated with considerable myelotoxicity leading to longlasting aplasias of about 6 weeks. However, after intensive induction treatment, high-dose chemotherapy in remission may become practicable using autologous stem cell rescue and may contribute to a further improvement of the outcome in poor risk as well as average patients with AML. These approaches are currently investigated by the German AMLCG. While there are clear limitations in the intensity of antineoplastic treatment for AML, as for other systemic malignancies, some further intensification may be possible and effective.
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- 2004
6. Acute Myeloid Leukemia (AML): The Role of Maintenance Chemo¬therapy
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Thomas Büchner, Wolfgang Hiddemann, Wolfgang E. Berdel, Bernhard Wörmann, Helmut Löffler, Claudia Schoch, Torsten Haferlach, Wolf-Dieter Ludwig, Georg Maschmeyer, Eva Lengelder, Peter Staib, Reinhard Andreesen, Leopold Balleisen, Detlef Haase, Hartmut Eimermacher, Carlo Aul, Herbert Rasche, Jens Uhlig, Andreas Grüneisen, Hans Edgar Reis, Joachim Hartlapp, Wolf-Dietrich Hirschmann, Hans-Josef Weh, Hermann-Josef Pielken, Winfried Gassmann, Andrea Schumacher, Maria-Cristina Sauerland, and Achim Heinecke for the German AML Cooperative Group
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maintenance therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 16 published multicenter trials, however, revealed the highest probabilities of relapse free survival (RFS) in the range of 35-42 % at 4-5 years only in patients assigned to maintenance treatment when adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS from 3 year maintenance following standard dose consolidation over that from consolidation alone (p
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- 2004
7. Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia
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Stefan K. Bohlander, Stephanie Schneider, Bernhard Wörmann, Marion Subklewe, Utz Krug, Tobias Herold, Victoria V. Grunwald, Wolfgang Hiddemann, Klaus H. Metzeler, Dennis Goerlich, Maria Cristina Sauerland, Andreas Faldum, Hanna Janke, Philipp A. Greif, Michaela Neusser, Karsten Spiekermann, Nikola P. Konstandin, Bianka Ksienzyk, Jan Braess, Maja Rothenberg-Thurley, Wolfgang E. Berdel, and Annika Dufour
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Adolescent ,Risk Assessment ,Article ,Acute myeloid leukaemia ,Young Adult ,European LeukemiaNet ,Internal medicine ,Genetics research ,CEBPA ,Humans ,Medicine ,Cancer genetics ,Survival rate ,Aged ,Aged, 80 and over ,business.industry ,Myeloid leukemia ,Induction chemotherapy ,Induction Chemotherapy ,Hematology ,Middle Aged ,Translational research ,Prognosis ,medicine.disease ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Risk factors ,Oncology ,Mutation ,Cohort ,Female ,business - Abstract
The revised 2017 European LeukemiaNet (ELN) recommendations for genetic risk stratification of acute myeloid leukemia have been widely adopted, but have not yet been validated in large cohorts of AML patients. We studied 1116 newly diagnosed AML patients (age range, 18–86 years) who had received induction chemotherapy. Among 771 patients not selected by genetics, the ELN-2017 classification re-assigned 26.5% of patients into a more favorable or, more commonly, a more adverse-risk group compared with the ELN-2010 recommendations. Forty percent of the cohort, and 51% of patients ≥60 years, were classified as adverse-risk by ELN-2017. In 599 patients CEBPA mutations or inv(16) had particularly favorable outcomes, while patients with mutated TP53 and a complex karyotype had especially poor prognosis. DNMT3A mutations associated with inferior OS within each ELN-2017 risk group. Our results validate the prognostic significance of the revised ELN-2017 risk classification in AML patients receiving induction chemotherapy across a broad age range. Further refinement of the ELN-2017 risk classification is possible.
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- 2020
8. Response assessment in acute myeloid leukemia by flow cytometry supersedes cytomorphology at time of aplasia, amends cases without molecular residual disease marker and serves as an independent prognostic marker at time of aplasia and post-induction
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Maja Rothenberg-Thurley, Maria-Cristina Sauerland, Marion Subklewe, Thomas Köhnke, Sandra Rechkemmer, Veit Bücklein, Stephanie Schneider, Karsten Spiekermann, Klaus H. Metzeler, and Wolfgang Hiddemann
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Myeloid ,Neoplasm, Residual ,Flow cytometry ,Immunophenotyping ,Bone Marrow ,medicine ,Neoplasm ,Humans ,Online Only Articles ,Survival analysis ,Aged ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Myeloid leukemia ,Hematology ,Aplasia ,Middle Aged ,medicine.disease ,Flow Cytometry ,Prognosis ,Survival Analysis ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Female ,business ,Biomarkers - Published
- 2019
9. A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia
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Johanna Tischer, Marion Subklewe, Wolfgang Hiddemann, Julia Phillippou-Massier, Dennis Görlich, Vindi Jurinovic, Helmut Blum, Nikola P. Konstandin, Stefan K. Bohlander, Tobias Herold, Bianka Ksienzyk, Philipp A. Greif, Stefanos A. Bamopoulos, Wolfgang E. Berdel, Klaus H. Metzeler, Stefan Krebs, Aarif M. N. Batcha, Maja Rothenberg-Thurley, Ulrich Mansmann, Karsten Spiekermann, Maria Cristina Sauerland, Stephanie Schneider, Jan Braess, Luise Hartmann, Bernhard Wörmann, and Susanne Amler
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0301 basic medicine ,Oncology ,Acute Myeloid Leukemia ,medicine.medical_specialty ,Myeloid ,Drug resistance ,Article ,03 medical and health sciences ,Cytogenetics ,Internal medicine ,medicine ,Humans ,Survival analysis ,business.industry ,Cytarabine ,Myeloid leukemia ,Hematology ,medicine.disease ,Gene expression profiling ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Predictive value of tests ,Cohort ,business - Abstract
Primary therapy resistance is a major problem in acute myeloid leukemia treatment. We set out to develop a powerful and robust predictor for therapy resistance for intensively treated adult patients. We used two large gene expression data sets (n=856) to develop a predictor of therapy resistance, which was validated in an independent cohort analyzed by RNA sequencing (n=250). In addition to gene expression markers, standard clinical and laboratory variables as well as the mutation status of 68 genes were considered during construction of the model. The final predictor (PS29MRC) consisted of 29 gene expression markers and a cytogenetic risk classification. A continuous predictor is calculated as a weighted linear sum of the individual variables. In addition, a cut off was defined to divide patients into a high-risk and a low-risk group for resistant disease. PS29MRC was highly significant in the validation set, both as a continuous score (OR=2.39, P=8.63·10−9, AUC=0.76) and as a dichotomous classifier (OR=8.03, P=4.29·10−9); accuracy was 77%. In multivariable models, only TP53 mutation, age and PS29MRC (continuous: OR=1.75, P=0.0011; dichotomous: OR=4.44, P=0.00021) were left as significant variables. PS29MRC dominated all models when compared with currently used predictors, and also predicted overall survival independently of established markers. When integrated into the European LeukemiaNet (ELN) 2017 genetic risk stratification, four groups (median survival of 8, 18, 41 months, and not reached) could be defined (P=4.01·10−10). PS29MRC will make it possible to design trials which stratify induction treatment according to the probability of response, and refines the ELN 2017 classification.
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- 2018
10. Mediation analysis reveals common mechanisms of RUNX1 point mutations and RUNX1/RUNX1T1 fusions influencing survival of patients with acute myeloid leukemia
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Wolfgang Hiddemann, Klaus H. Metzeler, Sören Lehmann, Tobias Herold, Maria Cristina Sauerland, Karsten Spiekermann, Wolfgang E. Berdel, Anne-Laure Boulesteix, Bernhard Wörmann, Maja Rothenberg-Thurley, Jan Braess, Susanne Amler, Roman Hornung, Stefan K. Bohlander, Sylvain Mareschal, Vindi Jurinovic, Stefanos A. Bamopoulos, and Aarif M. N. Batcha
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Mediation (statistics) ,Myeloid ,lcsh:Medicine ,Biology ,Biostatistics ,Article ,Fusion gene ,03 medical and health sciences ,chemistry.chemical_compound ,RUNX1 Translocation Partner 1 Protein ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Point Mutation ,Hematologi ,lcsh:Science ,Multidisciplinary ,Gene Expression Profiling ,lcsh:R ,RUNX1T1 ,Myeloid leukemia ,Hematology ,medicine.disease ,Gene expression profiling ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,RUNX1 ,chemistry ,Core Binding Factor Alpha 2 Subunit ,embryonic structures ,lcsh:Q ,Gene Fusion - Abstract
Alterations of RUNX1 in acute myeloid leukemia (AML) are associated with either a more favorable outcome in the case of the RUNX1/RUNX1T1 fusion or unfavorable prognosis in the case of point mutations. In this project we aimed to identify genes responsible for the observed differences in outcome that are common to both RUNX1 alterations. Analyzing four AML gene expression data sets (n = 1514), a total of 80 patients with RUNX1/RUNX1T1 and 156 patients with point mutations in RUNX1 were compared. Using the statistical tool of mediation analysis we identified the genes CD109, HOPX, and KIAA0125 as candidates for mediator genes. In an analysis of an independent validation cohort, KIAA0125 again showed a significant influence with respect to the impact of the RUNX1/RUNX1T1 fusion. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis. Our analysis demonstrates that mediation analysis is a powerful tool in the identification of regulative networks in AML subgroups and could be further used to characterize the influence of genetic alterations.
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- 2018
11. Acute myeloid leukemia with del(9q) is characterized by frequent mutations of NPM1, DNMT3A, WT1 and low expression of TLE4
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Tobias, Herold, Klaus H, Metzeler, Sebastian, Vosberg, Luise, Hartmann, Vindi, Jurinovic, Sabrina, Opatz, Nikola P, Konstandin, Stephanie, Schneider, Evelyn, Zellmeier, Bianka, Ksienzyk, Alexander, Graf, Stefan, Krebs, Helmut, Blum, Maria, Cristina Sauerland, Thomas, Büchner, Wolfgang E, Berdel, Bernhard J, Wörmann, Ulrich, Mansmann, Wolfgang, Hiddemann, Stefan K, Bohlander, Karsten, Spiekermann, and Philipp A, Greif
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Adult ,Male ,Adolescent ,DNA Methyltransferase 3A ,Cohort Studies ,Young Adult ,Biomarkers, Tumor ,Humans ,Exome ,DNA (Cytosine-5-)-Methyltransferases ,WT1 Proteins ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Chromosome Aberrations ,High-Throughput Nucleotide Sequencing ,Nuclear Proteins ,Middle Aged ,Prognosis ,Repressor Proteins ,Survival Rate ,Leukemia, Myeloid, Acute ,Mutation ,Female ,Chromosome Deletion ,Chromosomes, Human, Pair 9 ,Nucleophosmin ,Follow-Up Studies - Abstract
Deletions of the long arm of chromosome 9 [del(9q)] are a rare but recurring aberration in acute myeloid leukemia (AML). Del(9q) can be found as the sole abnormality or in combination with other cytogenetic aberrations such as t(8;21) and t(15;17). TLE1 and TLE4 were identified to be critical genes contained in the 9q region. We performed whole exome sequencing of 5 patients with del(9q) as the sole abnormality followed by targeted amplicon sequencing of 137 genes of 26 patients with del(9q) as sole or combined with other aberrations. We detected frequent mutations in NPM1 (10/26; 38%), DNMT3A (8/26; 31%), and WT1 (8/26; 31%) but only few FLT3-ITDs (2/26; 8%). All mutations affecting NPM1 and DNMT3A were exclusively identified in patients with del(9q) as the sole abnormality and were significantly more frequent compared to 111 patients classified as intermediate-II according to the European LeukemiaNet (10/14, 71% vs. 22/111, 20%; P 0.001, 8/14, 57% vs. 26/111, 23%; P = 0.02). Furthermore, we identified DNMT3B to be rarely but recurrently targeted by truncating mutations in AML. Gene expression analysis of 13 patients with del(9q) and 454 patients with normal karyotype or various cytogenetic aberrations showed significant down regulation of TLE4 in patients with del(9q) (P = 0.02). Interestingly, downregulation of TLE4 was not limited to AML with del(9q), potentially representing a common mechanism in AML pathogenesis. Our comprehensive genetic analysis of the del(9q) subgroup reveals a unique mutational profile with the frequency of DNMT3A mutations in the del(9q) only subset being the highest reported so far in AML, indicating oncogenic cooperativity. © 2016 Wiley Periodicals, Inc.
- Published
- 2017
12. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation
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Bianka Ksienzyk, Stephan Wolf, Karl-Peter Hopfner, Alexander Graf, Sabrina Opatz, Stefan Krebs, Helmut Blum, Maria Cristina Sauerland, Philipp A. Greif, Christian Wichmann, Jan Moritz Middeke, Evelyn Zellmeier, Bernhard Wörmann, Friedrich Stölzel, Wolfgang E. Berdel, Nikola P. Konstandin, Tobias Herold, Sebastian Vosberg, Stefanos A. Bamopoulos, Christian Thiede, Karsten Spiekermann, Linping Chen-Wichmann, Thomas Büchner, Georg Leubolt, Carolin Preiss, Klaus H. Metzeler, Katrin Reiter, Stephanie Schneider, Luise Hartmann, Jan Braess, Sayantanee Dutta, Wolfgang Hiddemann, Kathrin Bräundl, and Stefan K. Bohlander
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0301 basic medicine ,Myeloid ,Oncogene Proteins, Fusion ,Molecular biology ,Chromosomes, Human, Pair 21 ,General Physics and Astronomy ,Chromosomal translocation ,medicine.disease_cause ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit ,Translocation, Genetic ,Fusion gene ,chemistry.chemical_compound ,RUNX1 Translocation Partner 1 Protein ,hemic and lymphatic diseases ,Cancer ,Mutation ,Multidisciplinary ,Gene Expression Regulation, Leukemic ,DNA-Binding Proteins ,Haematopoiesis ,Biological sciences ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,RUNX1 ,Core Binding Factor Alpha 2 Subunit ,Glycolysis ,Chromosomes, Human, Pair 8 ,Signal Transduction ,Lineage (genetic) ,Science ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Protein Domains ,Cell Line, Tumor ,medicine ,Genetics ,Humans ,Base Sequence ,Gene Expression Profiling ,RUNX1T1 ,General Chemistry ,Survival Analysis ,030104 developmental biology ,HEK293 Cells ,chemistry ,FOS: Biological sciences ,Transcription Factors - Abstract
The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion., The t(8;21) translocation is often found in acute myeloid leukaemia but is not sufficient for development of the disease. In this study, the authors identify frequent mutations in the transcriptional repressor, ZBTB7A, in these patients and show that the mutations reduce DNA binding activity.
- Published
- 2016
13. Molecular response assessment by quantitativerael-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies patients at high risk for relapse
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Marion Subklewe, Thomas Büchner, Michael Fiegl, Wolfgang E. Berdel, Wolfgang Hiddemann, Annika Dufour, Max Hubmann, Karsten Spiekermann, Maria-Cristina Sauerland, Stephanie Schneider, Thomas Köhnke, Jan Braess, Evelyn Zellmeier, Bernhard Wörmann, Stefan K. Bohlander, and Eva Hoster
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Real-Time Polymerase Chain Reaction ,Acute Myeloid Leukemia ,Mrd ,Minimal Residual Disease ,Npm1 ,Rt-pcr ,Young Adult ,Recurrence ,Risk Factors ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Prospective Studies ,Prospective cohort study ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Hazard ratio ,Nuclear Proteins ,Myeloid leukemia ,Retrospective cohort study ,Induction Chemotherapy ,Articles ,Hematology ,Middle Aged ,medicine.disease ,Minimal residual disease ,Surgery ,Survival Rate ,Clinical trial ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,Mutation ,Female ,business ,Nucleophosmin ,Follow-Up Studies - Abstract
Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal residual disease monitoring by quantitative real-time polymerase chain reaction analysis of NPM1 mutations in patients treated in the AMLCG 1999, 2004 and 2008 trials. Minimal residual disease was monitored - in aplasia, after induction therapy, after consolidation therapy, and during follow-up - in 588 samples from 158 patients positive for NPM1 mutations A, B and D (with a sensitivity of 10(-6)). One hundred and twenty-seven patients (80.4%) achieved complete remission after induction therapy and, of these, 56 patients (44.1%) relapsed. At each checkpoint, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 was associated with a high hazard ratio of 4.26 and the highest sensitivity of 76% for the prediction of relapse. This was reflected in a cumulative incidence of relapse after 2 years of 77.8% for patients with ratios above the cut-off versus 26.4% for those with ratios below the cut-off. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separated the cohort into two prognostic groups with a cumulative incidence of relapse of 76% versus 6% after 2 years. Our data demonstrate that in addition to pre-therapeutic factors, the course of minimal residual disease in an individual is an important prognostic factor and could be included in clinical trials for the guidance of post-remission therapy. The trials from which data were obtained were registered at www.clinicaltrials.gov (#NCT01382147, #NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230).
- Published
- 2014
14. Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia
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Annika Dufour, Gudrun Mellert, Guido Marcucci, Eva Hoster, Kati Maharry, Bernhard J. Woermann, Wolfgang E. Berdel, Stefan K. Bohlander, Maria Cristina Sauerland, Michaela Feuring-Buske, Bianka Ksienzyk, Utz Krug, Stephanie Schneider, Evelyn Zellmeier, Christian Buske, Clara D. Bloomfield, Purvi M. Kakadia, Michael Unterhalt, Tobias Benthaus, Klaus H. Metzeler, Karsten Spiekermann, Achim Heinecke, Wolfgang Hiddemann, Thomas Buechner, Jan Braess, and Friederike Pastore
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Oncology ,Male ,Cancer Research ,Myeloid ,Time Factors ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,Recurrence ,Risk Factors ,Germany ,CEBPA ,Medicine ,Aged, 80 and over ,Age Factors ,Myeloid leukemia ,Nuclear Proteins ,ORIGINAL REPORTS ,Middle Aged ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Phenotype ,Treatment Outcome ,Cytogenetic Analysis ,Female ,Nucleophosmin ,Adult ,medicine.medical_specialty ,NPM1 ,Adolescent ,Risk Assessment ,Disease-Free Survival ,Decision Support Techniques ,Young Adult ,Predictive Value of Tests ,Internal medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,Proportional Hazards Models ,Performance status ,business.industry ,Proportional hazards model ,Cancer ,Reproducibility of Results ,medicine.disease ,fms-Like Tyrosine Kinase 3 ,Immunology ,Mutation ,CCAAT-Enhancer-Binding Proteins ,business - Abstract
Purpose Cytogenetically normal (CN) acute myeloid leukemia (AML) is the largest and most heterogeneous cytogenetic AML subgroup. For the practicing clinician, it is difficult to summarize the prognostic information of the growing number of clinical and molecular markers. Our purpose was to develop a widely applicable prognostic model by combining well-established pretreatment patient and disease characteristics. Patients and Methods Two prognostic indices for CN-AML (PINA), one regarding overall survival (OS; PINAOS) and the other regarding relapse-free survival (RFS; PINARFS), were derived from data of 572 patients with CN-AML treated within the AML Cooperative Group 99 study ( www.aml-score.org ). Results On the basis of age (median, 60 years; range, 17 to 85 years), performance status, WBC count, and mutation status of NPM1, CEBPA, and FLT3-internal tandem duplication, patients were classified into the following three risk groups according to PINAOS and PINARFS: 29% of all patients and 32% of 381 responding patients had low-risk disease (5-year OS, 74%; 5-year RFS, 55%); 56% of all patients and 39% of responding patients had intermediate-risk disease (5-year OS, 28%; 5-year RFS, 27%), and 15% of all patients and 29% of responding patients had high-risk disease (5-year OS, 3%; 5-year RFS, 5%), respectively. PINAOS and PINARFS stratified outcome within European LeukemiaNet genetic groups. Both indices were confirmed on independent data from Cancer and Leukemia Group B/Alliance trials. Conclusion We have developed and validated, to our knowledge, the first prognostic indices specifically designed for adult patients of all ages with CN-AML that combine well-established molecular and clinical variables and that are easily applicable in routine clinical care. The integration of both clinical and molecular markers could provide a basis for individualized patient care through risk-adapted therapy of CN-AML.
- Published
- 2014
15. RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with poor prognosis and up-regulation of lymphoid genes
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Thomas Büchner, Zlatana Pasalic, Jan Braess, Wolfgang E. Berdel, Friederike Schneider, Wolfgang Hiddemann, Nikola P. Konstandin, Purvi M. Kakadia, Tobias Herold, Bianka Ksienzyk, Maria Cristina Sauerland, Bernhard J. Woermann, Stephanie Schneider, Philipp A. Greif, Stefan K. Bohlander, Karsten Spiekermann, Klaus H. Metzeler, and Annika Dufour
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Adult ,Male ,NPM1 ,Lineage (genetic) ,Biology ,medicine.disease_cause ,Pathogenesis ,Cohort Studies ,chemistry.chemical_compound ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,Survival rate ,In Situ Hybridization, Fluorescence ,Adaptor Proteins, Signal Transducing ,Aged ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,Mutation ,Myelodysplastic syndromes ,Gene Expression Profiling ,Remission Induction ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Rate ,Leukemia, Myeloid, Acute ,RUNX1 ,chemistry ,Core Binding Factor Alpha 2 Subunit ,embryonic structures ,Runx1 ,Mutations ,Acute Myeloid Leukemia ,Cancer research ,Female ,Original Articles and Brief Reports ,Nucleophosmin ,Follow-Up Studies - Abstract
Background The RUNX1 ( AML1 ) gene is a frequent mutational target in myelodysplastic syndromes and acute myeloid leukemia. Previous studies suggested that RUNX1 mutations may have pathological and prognostic implications. Design and Methods We screened 93 patients with cytogenetically normal acute myeloid leukemia for RUNX1 mutations by capillary sequencing of genomic DNA. Mutation status was then correlated with clinical data and gene expression profiles. Results We found that 15 out of 93 (16.1%) patients with cytogenetically normal acute myeloid leukemia had RUNX1 mutations. Seventy-three patients were enrolled in the AMLCG-99 trial and carried ten RUNX1 mutations (13.7%). Among these 73 patients RUNX1 mutations were significantly associated with older age, male sex, absence of NPM1 mutations and presence of MLL -partial tandem duplications. Moreover, RUNX1 -mutated patients had a lower complete remission rate (30% versus 73% P =0.01), lower relapse-free survival rate (3-year relapse-free survival 0% versus 30.4%; P =0.002) and lower overall survival rate (3-year overall survival 0% versus 34.4%; P
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- 2012
16. Induction Therapy by Ara-C Plus Daunorubicin Versus Ara-C plus Gemtuzumab Ozogamicin : Interim Analysis of a Randomized Phase II Trial of the SAL In Elderly Patients with Acute Myeloid Leukemia
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Richard Noppeney, Michael Mohr, Hubert Serve, Wolfgang E. Berdel, Rolf M. Mesters, Uta Brunnberg, Carsten Müller-Tidow, Gerhard Ehninger, Maria Cristina Sauerland, Heinz A. Duerk, Christiane Schulz, Thomas Büchner, Steffen Koschmieder, Ulrich Dührsen, Torsten Kessler, and Utz Krug
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Oncology ,medicine.medical_specialty ,Chemotherapy ,education.field_of_study ,Daunorubicin ,business.industry ,Gemtuzumab ozogamicin ,medicine.medical_treatment ,Immunology ,Population ,Medizin ,Phases of clinical research ,Myeloid leukemia ,Cell Biology ,Hematology ,Off-label use ,Interim analysis ,Biochemistry ,Internal medicine ,medicine ,business ,education ,medicine.drug - Abstract
Abstract 335 Purpose. Standard chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival of only 60 years) patients with relapsed AML and shows low cardiac toxicity. The purpose of the randomized phase II study reported here was to compare the antileukemic activity of a standard combination of ara-C (100 mg/m2/day c.i., days 1–7) and DNR (60 mg/m2 i.v., on days 3–5) (7+3) versus ara-C plus GO (6 mg/m2 i.v. on days 1 and 8) (7+GO) as the first course of induction therapy in AML patients at the age of 60 years and older. Patients and Methods. On the basis of the data from the AMLCG (JCO 27: 61–69, 2009) the study was powered to detect an increase of median event free survival (EFS) from 90 to 160 days and a prolongation of the median overall survival (OS) from 9 to >16 months with a power of 80% (alpha= .05), in order to obtain information as a basis for potential further phase III randomized studies. Primary objectives of the study were the achievement of blast clearance (< 5%) on day 16 after induction therapy onset and EFS. OS, complete response (CR) and tolerability were among the secondary objectives. 112 pts. entered the study, suffering from de novo AML, treatment-related secondary AML, AML with a history of MDS, and high-risk MDS. Median age of the patients was 69 years (range 60–83). Study protocol outlined a second induction course 7+3 in those pts. without blast clearance on day 16 and 2 courses of consolidation therapy with high-dose ara-C (1 g/m2 q 12 hours i.v., days 1, 3, 5) for patients in CR. We looked for balance of AML standard risk factors between both arms of the study. Results. The study was approved by the Ethical Board of the University of Muenster and the other participating institutions and written informed consent was obligatory by every pt. prior to entry on study. 58 pts. were randomized to induction therapy with 7+3 as the first course, whereas 54 pts. were randomized to receive 7+GO. All parameters evaluated are for the intent-to-treat population. There were no statistically significant differences between treatment arms in blast clearance (< 5%) on day 16 after treatment onset (7+3: 18 pts., 7+GO: 19 pts.), complete response (CR) rate (7+3: 53.5%, 7+GO: 61.1%), EFS (median for 7+3: 67 days, median for 7+GO: 172 days), or OS (median for 7+3: 9 months, median for 7+GO: 15 months). Toxicity profiles of the protocols were different with 4 pts. developing severe veno-occlusive disease in the 7+GO group. Conclusion. The study did not show a significant advantage of 7+GO over 7+3 as the first course of induction treatment in elderly pts. with AML. Ara-C and GO and ara-C and DNR have comparable antileukemic activity as the first course of induction. Ara-C and GO may represent an alternative, replacing non-targeted anthracyclines for induction therapy of elderly AML patients e.g. with significant cardiac comorbidities. Disclosures: Berdel: Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Mylotarg as first-line treatment in AML.
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- 2010
17. Related versus unrelated donor transplantation for high risk (HiRi) acute myeloid leukemia (AML) in first complete remission (CR1)
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Christoph Schmid, Thomas Büchner, Claudia Haferlach, Joachim Kienast, Bjorna Berning, Maria Cristina Sauerland, Rainer Schwerdtfeger, Renate Arnold, Peter Staib, Karin Kolbe, Hans-Jochem Kolb, Dietrich W. Beelen, Ernst Holler, Wolfgang Hiddemann, Albrecht Reichle, Wolfgang E. Berdel, and Matthias Stelljes
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Oncology ,medicine.medical_specialty ,business.industry ,Surrogate endpoint ,medicine.medical_treatment ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,law.invention ,Log-rank test ,Transplantation ,Randomized controlled trial ,law ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Observational study ,Sibling ,business - Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) from an HLA-identical sibling donor (SIB) is considered the preferred postremission therapy for younger patients with HiRi AML in CR1. The role of allo-SCT from volunteer unrelated donors (VUDs) is less clear and randomized controlled trials addressing this issue do not exist. We performed an observational landmark analysis on parallel cohorts of patients aged
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- 2007
18. Response assessment in acute myeloid leukemia by flow cytometry supersedes cytomorphology at time of aplasia, amends cases without molecular residual disease marker and serves as an independent prognostic marker at time of aplasia and post-induction
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Thomas Köhnke, Veit Bücklein, Sandra Rechkemmer, Stephanie Schneider, Maja Rothenberg-Thurley, Klaus H. Metzeler, Maria-Cristina Sauerland, Wolfgang Hiddemann, Karsten Spiekermann, and Marion Subklewe
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
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19. Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse
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Max Hubmann, Thomas Köhnke, Eva Hoster, Stephanie Schneider, Annika Dufour, Evelyn Zellmeier, Michael Fiegl, Jan Braess, Stefan K. Bohlander, Marion Subklewe, Maria-Cristina Sauerland, Wolfgang E. Berdel, Thomas Büchner, Bernhard Wörmann, Wolfgang Hiddemann, and Karsten Spiekermann
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal residual disease monitoring by quantitative real-time polymerase chain reaction analysis of NPM1 mutations in patients treated in the AMLCG 1999, 2004 and 2008 trials. Minimal residual disease was monitored - in aplasia, after induction therapy, after consolidation therapy, and during follow-up - in 588 samples from 158 patients positive for NPM1 mutations A, B and D (with a sensitivity of 10−6). One hundred and twenty-seven patients (80.4%) achieved complete remission after induction therapy and, of these, 56 patients (44.1%) relapsed. At each checkpoint, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 was associated with a high hazard ratio of 4.26 and the highest sensitivity of 76% for the prediction of relapse. This was reflected in a cumulative incidence of relapse after 2 years of 77.8% for patients with ratios above the cut-off versus 26.4% for those with ratios below the cut-off. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separated the cohort into two prognostic groups with a cumulative incidence of relapse of 76% versus 6% after 2 years. Our data demonstrate that in addition to pre-therapeutic factors, the course of minimal residual disease in an individual is an important prognostic factor and could be included in clinical trials for the guidance of post-remission therapy. The trials from which data were obtained were registered at www.clinicaltrials.gov (#NCT01382147, #NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230).
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- 2014
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20. Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia.
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Pastore F, Dufour A, Benthaus T, Metzeler KH, Maharry KS, Schneider S, Ksienzyk B, Mellert G, Zellmeier E, Kakadia PM, Unterhalt M, Feuring-Buske M, Buske C, Braess J, Sauerland MC, Heinecke A, Krug U, Berdel WE, Buechner T, Woermann B, Hiddemann W, Bohlander SK, Marcucci G, Spiekermann K, Bloomfield CD, and Hoster E
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- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, CCAAT-Enhancer-Binding Proteins genetics, DNA Mutational Analysis, Disease-Free Survival, Female, Genetic Predisposition to Disease, Germany, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation, Nuclear Proteins genetics, Nucleophosmin, Phenotype, Predictive Value of Tests, Proportional Hazards Models, Recurrence, Reproducibility of Results, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Young Adult, fms-Like Tyrosine Kinase 3 genetics, Cytogenetic Analysis, Decision Support Techniques, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Cytogenetically normal (CN) acute myeloid leukemia (AML) is the largest and most heterogeneous cytogenetic AML subgroup. For the practicing clinician, it is difficult to summarize the prognostic information of the growing number of clinical and molecular markers. Our purpose was to develop a widely applicable prognostic model by combining well-established pretreatment patient and disease characteristics., Patients and Methods: Two prognostic indices for CN-AML (PINA), one regarding overall survival (OS; PINAOS) and the other regarding relapse-free survival (RFS; PINARFS), were derived from data of 572 patients with CN-AML treated within the AML Cooperative Group 99 study (www.aml-score.org)., Results: On the basis of age (median, 60 years; range, 17 to 85 years), performance status, WBC count, and mutation status of NPM1, CEBPA, and FLT3-internal tandem duplication, patients were classified into the following three risk groups according to PINAOS and PINARFS: 29% of all patients and 32% of 381 responding patients had low-risk disease (5-year OS, 74%; 5-year RFS, 55%); 56% of all patients and 39% of responding patients had intermediate-risk disease (5-year OS, 28%; 5-year RFS, 27%), and 15% of all patients and 29% of responding patients had high-risk disease (5-year OS, 3%; 5-year RFS, 5%), respectively. PINAOS and PINARFS stratified outcome within European LeukemiaNet genetic groups. Both indices were confirmed on independent data from Cancer and Leukemia Group B/Alliance trials., Conclusion: We have developed and validated, to our knowledge, the first prognostic indices specifically designed for adult patients of all ages with CN-AML that combine well-established molecular and clinical variables and that are easily applicable in routine clinical care. The integration of both clinical and molecular markers could provide a basis for individualized patient care through risk-adapted therapy of CN-AML., (© 2014 by American Society of Clinical Oncology.)
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- 2014
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