137 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
- Full Text
- View/download PDF
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
- Full Text
- 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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- View/download PDF
5. Sex-Associated Differences in Frequencies and Outcome Prognostication of Recurrent Molecular Features in Adults with Acute Myeloid Leukemia (AML) (AMLCG, CALGB [Alliance])
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Michael P. Ozga, Deedra Nicolet, Krzysztof Mrózek, Selen Yilmaz, Jessica Kohlschmidt, Karilyn T. Larkin, James S. Blachly, Christopher C. Oakes, Jill Buss, Christopher J. Walker, Shelley Orwick, Vindi Jurinovic, Maja Rothenberg-Thurley, Annika Maria Dufour, Stephanie Schneider, Maria Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E. Berdel, Bernhard Josef Woermann, Wolfgang Hiddemann, Jan Braess, Marion Subklewe, Karsten Spiekermann, Andrew J. Carroll, William G. Blum, Bayard L. Powell, Jonathan E. Kolitz, Joseph O. Moore, Robert James Mayer, Richard M. Stone, Geoffrey L. Uy, Wendy Stock, Klaus H. Metzeler, H. Leighton Grimes, John C. Byrd, Nathan Salomonis, Tobias Herold, Alice S. Mims, and Ann-Kathrin Eisfeld
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. Secondary Neoplasms in AML Long-Term Survivors: Even More Cancer to Come?
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Anna Sophia Moret, Eva Telzerow, Maria Cristina Sauerland, Simon M. Krauss, Maja Rothenberg-Thurley, Friederike H.A. Mumm, Jan Braess, Bernhard J. Wörmann, Utz Krug, Wolfgang E. Berdel, Wolfgang Hiddemann, Karsten Spiekermann, Pia Heußner, Dennis Görlich, and Klaus H. Metzeler
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. German AMLCG-Survivorship Study: Anxiety and Depression Symptoms in AML Long-Term Survivors
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Dennis Görlich, Eva Telzerow, Maria Cristina Sauerland, Anna Sophia Moret, Maja Rothenberg-Thurley, Friederike H.A. Mumm, Susanne Amler, Wolfgang E. Berdel, Bernhard J. Wörmann, Utz Krug, Jan Braess, Pia Heußner, Wolfgang Hiddemann, Karsten Spiekermann, and Klaus H. Metzeler
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
8. Validation of the 2022 European Leukemianet Genetic Risk Stratification of Acute Myeloid Leukemia
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Christian Rausch, Maja Rothenberg-Thurley, Annika Maria Dufour, Stephanie Schneider, Hanna Gittinger, Maria Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E. Berdel, Bernhard Josef Woermann, Wolfgang Hiddemann, Jan Braess, Karsten Spiekermann, Tobias Herold, and Klaus H. Metzeler
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
9. Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia
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Aarif M. N. Batcha, Tobias Herold, Stefan K. Bohlander, Dennis Görlich, Bianka Ksienzyk, Wolfgang E. Berdel, Jan Braess, Wolfgang Hiddemann, Alexander Graf, Ulrich Mansmann, Stephanie Schneider, Maria Cristina Sauerland, Bernhard J. Woermann, Karsten Spiekermann, Stefan Krebs, Hanna Janke, Nikola P. Konstandin, Vindi Jurinovic, Julia Philippou-Massier, Klaus H. Metzeler, Stefan Canzar, Maja Rothenberg-Thurley, Stefanos A. Bamopoulos, and Helmut Blum
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Adult ,Male ,0301 basic medicine ,Gene isoform ,Cancer Research ,Myeloid ,Adolescent ,RNA Splicing ,Mutant ,Biology ,medicine.disease_cause ,Cohort Studies ,Young Adult ,03 medical and health sciences ,Splicing factor ,0302 clinical medicine ,medicine ,Humans ,Gene ,Aged ,Aged, 80 and over ,Mutation ,Serine-Arginine Splicing Factors ,Myeloid leukemia ,Hematology ,Middle Aged ,Phosphoproteins ,Splicing Factor U2AF ,medicine.disease ,Haematopoiesis ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,RNA splicing ,Cancer research ,Female ,RNA Splicing Factors ,Myeloid leukaemia - Abstract
Previous studies have demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies. Their clinical characteristics and aberrant splicing patterns have been explored in myelodysplasia, however, their functional consequences in acute myeloid leukaemia are largely unknown. The aim of this study was the comprehensive clinical and functional analysis of mutations in the three most commonly afflicted splicing factor genes: SRSF2 , U2AF1 and SF3B1 . To this end, we examined the prognostic role of splicing factor mutations in two large independent cohorts, encompassing a total of 2678 acute myeloid leukaemia patients treated with intensive chemotherapy. The clinical analysis was complemented by RNA-sequencing of 246 patients to identify targets of splicing dysregulation. Results were validated in an additional RNA-sequencing dataset of 177 patients. Patients with splicing factor mutations show inferior relapse-free and overall survival, however, these mutations do not represent independent prognostic markers. Differential isoform expression analysis revealed a characteristic expression profile for each splicing factor mutation with a strong dysregulation of several isoforms. Furthermore, by establishing a custom differential splice junction usage pipeline we accurately detected aberrant splicing in splicing factor mutated samples. Mutated samples were characterized by predominantly decreased splice junction utilization of a large number of genes. A large proportion of differentially used spliced junctions were novel. Targets of splicing dysregulation included several genes with a known role in acute myeloid leukaemia. In SRSF2 (P95H) mutants we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Taken together, our findings suggest that splicing factor mutations does not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.
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- 2020
10. The clinical mutatome of core binding factor leukemia
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Jan Moritz Middeke, Alexander Graf, Nikola P. Konstandin, Stefan Krebs, Stefan K. Bohlander, Wolfgang E. Berdel, Alwin Krämer, Sebastian Vosberg, Stephanie Schneider, Bernhard Wörmann, Philipp A. Greif, Gerhard Ehninger, Luise Hartmann, Karsten Spiekermann, Dennis Görlich, Sebastian Tschuri, Klaus H. Metzeler, Sabrina Opatz, Helmut Blum, Maria Cristina Sauerland, Christian Thiede, Christine Wang, Friedrich Stölzel, Kathrin Bräundl, Bianka Ksienzyk, Christoph Röllig, Jan Braess, Wolfgang Hiddemann, Johannes Schetelig, Tobias Herold, and Stefanos A. Bamopoulos
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Adult ,Male ,Cancer Research ,Myeloid ,Adolescent ,medicine.medical_treatment ,Core binding factor ,Article ,Acute myeloid leukaemia ,Targeted therapy ,Young Adult ,chemistry.chemical_compound ,hemic and lymphatic diseases ,medicine ,MYH11 ,Humans ,Cancer genetics ,Aged ,Aged, 80 and over ,business.industry ,Core Binding Factors ,RUNX1T1 ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Oncology ,RUNX1 ,chemistry ,Mutation ,Cancer research ,Female ,business - Abstract
The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block 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 ZBTB7A being 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 DHX15 and 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.
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- 2020
11. 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
12. 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
- Published
- 2004
13. 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.
- Published
- 2020
14. 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
15. Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older
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Victoria V. Prassek, Hanna Janke, Bianka Ksienzyk, Nikola P. Konstandin, Jan Braess, Stephan K. Bohlander, Wolfgang Hiddemann, Marion Subklewe, Andreas Faldum, Tobias Herold, Wolfgang E. Berdel, Maja Rothenberg-Thurley, Bernhard Wörmann, Dennis Goerlich, Maria Cristina Sauerland, Stephanie Schneider, Karsten Spiekermann, Klaus H. Metzeler, and Utz Krug
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Male ,0301 basic medicine ,medicine.medical_specialty ,NPM1 ,Disease ,medicine.disease_cause ,Risk Assessment ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Mutation ,business.industry ,Cytogenetics ,Nuclear Proteins ,Induction chemotherapy ,Myeloid leukemia ,Hematology ,Isocitrate Dehydrogenase ,Survival Rate ,Leukemia, Myeloid, Acute ,Editorial ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,Genetic marker ,030220 oncology & carcinogenesis ,Cohort ,Female ,business ,Nucleophosmin - Abstract
A cute myeloid leukemia is a disease of the elderly (median age at diagnosis, 65–70 years). The prognosis of older acute myeloid leukemia patients is generally poor. While genetic markers have become important tools for risk stratification and treatment selection in young and middle-aged patients, their applicability in very old patients is less clear. We sought to validate existing genetic risk classification systems and identify additional factors associated with outcomes in intensively treated patients aged ≥75 years. In 151 patients who received induction chemotherapy in the AMLCG-1999 trial, we investigated recurrently mutated genes using a targeted sequencing assay covering 64 genes. The median number of mutated genes per patient was four. The most commonly mutated genes were TET2 (42%), DNMT3A (35%), NPM1 (32%), SRSF2 (25%) and ASXL1 (21%). The complete remission rate was 44% and the 3-year survival was 21% for the entire cohort. While adverse-risk cytogenetics (MRC classification) were associated with shorter overall survival (P=0.001), NPM1 and FLT3-ITD mutations (present in 18%) did not have a significant impact on overall survival. Notably, none of the 13 IDH1-mutated patients (9%) reached complete remission. Consequently, the overall survival of this subgroup was significantly shorter than that of IDH1-wildtype patients (P
- Published
- 2018
16. 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.
- Published
- 2018
17. Quality of Life and Life Satisfaction in AML Long-Term Survivors: Primary Results of the AMLCG-Survivorship Study
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Dennis Görlich, Wolfgang E. Berdel, Maria Cristina Sauerland, Anna Sophia Moret, Karsten Spiekermann, Wolfgang Hiddemann, Maja Rothenberg-Thurley, Jan Braess, Klaus H. Metzeler, Utz Krug, Eva Telzerow, Bernhard Wörmann, Pia Heußner, Susanne Amler, and Friederike Mumm
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Gerontology ,Quality of life (healthcare) ,business.industry ,Survivorship curve ,Immunology ,Life satisfaction ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,Term (time) - Abstract
Introduction An increasing proportion of patients with Acute Myeloid Leukemia (AML) become long-term survivors. Somatic and psycho-social outcomes are therefore becoming increasingly important, but little is known about the long-term effects of the disease and its treatment. Methods We designed a comprehensive analysis of AML survivorship outcomes including psycho-social well-being and somatic health status and conducted a questionnaire-based study collecting data from AML long term survivors (AML-LTS) and their physicians. This report focuses on overall and health-related quality of life. Somatic, especially cardiovascular, morbidity in AML-LTS are reported separately (Moret et al.). The primary aim of this study was to compare quality of life (QoL, measured by the FACT-G questionnaire) and general and health-related life satisfaction (gLS/hLS, measured by the FLZ-M questionnaire) of AML-LTS with normative data of German adults who were not diagnosed with AML (Holzner et al. 2009; Daig et al. 2009). FLZ-M and FACT-G scores were standardized relative to the normal population mean and standard deviation, stratified by sex and age. These z-scores were then tested against the fixed value 0 (indicating no difference between AML-LTS and the general population) using Mann-Whitney U-tests. Our statistical design incorporated a sequentially rejective testing procedure to maintain the multiple testing significance level at 5%, using a graphical model as described by Bretz et al. (2009). Results 427 former AML patients who had been enrolled in AMLCG trials (AMLCG-1999, AMLCG-2004, AMLCG-2008) or the AMLCG patient registry, participated in this study between 5 and 18.6 years [y] after their initial AML diagnosis (median, 11.3y). Median age of AML-LTS was 61y (range 28y-93y), and 56% were female. Thirty-eight percent of participants had been treated with chemotherapy alone, while 62% received at least one allogeneic stem cell transplant (alloSCT). A relapse occurred in 24% of the participants. Unexpectedly, quality of life and general life satisfaction summary scores were significantly higher in AML-LTS (p Notably, a subgroup of participants (26%) reported poor physical well-being (PWB), indicated by a FACT PWB subscore more than one standard deviation (SD) below the age- and sex-matched general population value (Figure A). This resulted in poor overall QoL (i.e. >1 SD below normal) for 13% of the participants (Figure B). To identify factors potentially associated with poor overall QoL, we constructed a logistic regression model including pre-specified cofactors (age, sex, time since initial diagnosis, relapse and alloSCT) and additional covariables that associated with QoL in univariate analyses (Table C). We found that participants with younger age, male sex, lower educational level, shorter time since diagnosis and a altered financial situation reported significantly lower QoL. No influence was found for other characteristics including treatment (alloSCT vs. no alloSCT), previous relapse, or de novo vs. secondary or therapy-related AML. Discussion Unlike previous studies of AML survivorship, our large cohort included a diverse spectrum of patients regarding age, time since diagnosis, and treatment modalities, which allows for new insight into long-term quality of life. Our study establishes that overall QoL in AML long-term survivors is comparable to the general population. Improvement of QoL continues beyond five years post diagnosis. Importantly, disease- and treatment-related factors, such as prior relapse or status post allogeneic transplantation, are not associated with overall QoL. However, we were able to identify risk factors for worse QoL (younger age, male sex, alteration of the financial situation), delineating a subgroup of patients that may still have a need for targeted psycho-social interventions five or more years after an AML diagnosis. Figure 1 Figure 1. Disclosures Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: Janssen: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler: AbbVie: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding.
- Published
- 2021
18. High Prevalence of CHF and Diabetes in AML Long-Term Survivors - a Patient Forever?
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Dennis Görlich, Wolfgang Hiddemann, Klaus Kraywinkel, Maria Cristina Sauerland, Elke Burgard, Bernhard Wörmann, Eva Telzerow, Maja Rothenberg-Thurley, Jan Braess, Klaus H. Metzeler, Friederike Mumm, Pia Heußner, Anna Sophia Moret, Wolfgang E. Berdel, Karsten Spiekermann, and Utz Krug
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Pediatrics ,medicine.medical_specialty ,High prevalence ,business.industry ,Diabetes mellitus ,Immunology ,Medicine ,Cell Biology ,Hematology ,business ,medicine.disease ,Biochemistry ,Term (time) - Abstract
Introduction: As outcomes of patients with acute myeloid leukemia (AML) have improved over the past decades, the fraction of patients surviving long-term is increasing. Information on long-term somatic and psycho-social health consequences of AML and its treatment is sparse. Previous studies suggested a higher prevalence of cardiovascular diseases in AML survivors, especially those treated with allogeneic stem cell transplantation (alloHSCT). The aim of our study was to perform a multi-dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on somatic, especially cardiovascular, morbidity in AML-LTS. Overall and health-related quality of life are reported separately (Telzerow et al.). Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessment by the patients' physicians, and medical and laboratory reports. An age- and sex-matched control cohort was derived from German population-based health surveys (Robert Koch Institute, DEGS1 survey; n=6013; persons diagnosed with leukemia [n=11] were excluded). Results: 427 AML-LTS, aged 28 to 93 years, participated in this study. Data on somatic health status is available for 355 survivors, 5 to 19 years after their AML diagnosis. Thirty-eight percent of survivors were treated with chemotherapy with or without an autologous transplant (autoHSCT), whereas 62% had undergone alloHSCT. Focusing on cardiovascular diseases and risk factors, we found that that 49% of AML-LTS had hypertension, 33% had hypercholesterolemia, 15% had type 1/2 diabetes, 10% had congestive heart failure (CHF), and 9% had coronary artery disease (Figure A). The mean body-mass index (BMI) of AML-LTS was 26.7, similar to the DEGS1 cohort (mean BMI, 26.8). Next, we compared the prevalence of cardiovascular diseases and risk factors between AML-LTS and the general German population (represented by the DEGS1 sample), using multivariate models adjusting for age and sex (Table B). Compared to persons not diagnosed with leukemia, AML survivors had similar risks of hypertension, coronary heart disease and myocardial infarction. Prevalence of diagnosed hypercholesterolemia was higher in AML-LTS compared to non-AML controls. In addition, AML-LTS had a 2-fold higher risk of having type 1/2 diabetes, and a 3.5-fold increased risk of CHF compared to the general population. To identify factors associated with the increased risks of diabetes and CHF among AML-LTS, we constructed multivariate models incorporating patient- and treatment related covariables (age, sex, BMI, smoking, prior AML relapse, treatment [chemotherapy + autoHSCT vs. alloHSCT], and type of leukemia [de novo versus secondary / therapy-related]). We found an increased risk of CHF for AML-LTS who had had a relapse (OR, 3.16; 95% CI: 1.46 - 6.83; P=0.004) and, in trend, for patients with sAML or tAML (OR 2.19; 95%CI: 0.92 - 5.22, P=0.076). In addition, we found an increased risk of type 1/2 diabetes for AML-LTS who are smokers (OR: 3.43; 95% CI: 1.43 - 8.21; p: 0.006). Disease- or treatment-related factors did not significantly associate with any of the other comorbidities we studied. Conclusion: To the best of our knowledge, this is the largest analysis of somatic health outcomes in AML-LTS. Strengths of our study include the relatively large cohort representing a wide age range, the long follow-up period of 5 to nearly 20 years, and the heterogeneity regarding therapy regimens (chemotherapy + autoHSCT vs. alloHSCT). We found that, compared to the general population, AML-LTS have increased risks for CHF and diabetes, but not for hypertension or coronary artery disease. We identified AML relapse as a risk factor for the development of CHF, suggesting that cumulative chemotherapy exposure might be causally involved. On the other hand, we found no treatment- and disease-related risk factors that might explain the higher prevalence of diabetes in AML-LTS. Notably, AML-LTS who had undergone alloHSCT did not have increased risks of CHF, cardiovascular disease, hypertension or diabetes, compared to survivors treated with chemotherapy only. Our results may guide future recommendations for follow-up and inform personalized treatment decisions. Figure 1 Figure 1. Disclosures Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: Janssen: Research Funding; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; AbbVie: Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Pfizer: Consultancy; Astellas: Honoraria.
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- 2021
19. Multi-Dimensional Analysis of Adult Acute Myeloid Leukemia (AML) Landscape Cross-Continents Reveals Age Associated Trends in Mutations and Outcomes
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Wolfgang Hiddemann, Christopher C. Oakes, Dennis Görlich, Aarif M. N. Batcha, Alice S. Mims, Shelley Orwick, Stephanie Schneider, Maria Cristina Sauerland, Christopher J. Walker, Karilyn Larkin, Richard Stone, Vindi Jurinovic, Maja Rothenberg-Thurley, Klaus H. Metzeler, Joseph O. Moore, William Blum, James S. Blachly, Andrew J. Carroll, Karsten Spiekermann, Bernhard J. Woermann, Utz Krug, John C. Byrd, Jessica Kohlschmidt, Jan Braess, Richard A. Larson, Deedra Nicolet, Robert J. Mayer, Wolfgang E. Berdel, Bayard L. Powell, Jonathan E. Kolitz, Ann-Kathrin Eisfeld, Monica Cusan, Krzysztof Mrózek, and Tobias Herold
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Oncology ,medicine.medical_specialty ,Internal medicine ,Immunology ,medicine ,Adult Acute Myeloid Leukemia ,Cell Biology ,Hematology ,Biology ,Multi dimensional analysis ,Biochemistry - Abstract
Background: AML is a disease affecting predominantly older patients (pts), but does occur across the entire age spectrum; younger adults [age Methods: We analyzed the molecular profiles of 2,823 adult AML pts enrolled onto clinical frontline protocols of 2 large cooperative study groups from 2 continents [US, Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology (Alliance), n=1743; Germany, AML Cooperative Group [AMLCG], n=1080] between 1986 and 2016. Treatment of all pts included intensive induction therapy, whereas pts enrolled on CALGB/Alliance protocols precluded allogeneic transplantation in 1 st complete remission. Pts in both cohorts were profiled for molecular features via targeted sequencing platforms. Frequencies of mutations genes and selected cytogenetic findings were then calculated in both datasets for the group of pts aged 18-24 y and for older pts by 5-year intervals until the age of 74 y and for pts older than 75 y. We also analyzed survival outcomes of 1,669 AML pts younger than 60 y using the same age intervals up to age 59 y. Results: Our side-by-side analysis shows remarkable congruence of results between German and US pt populations. Selected AML-associated gene mutations (mutation frequency ≥4%) and recurrent cytogenetic abnormalities followed 3 basic distribution patterns across the age spectrum (Fig. 1A): group 1 with increasing frequency with increasing age [ASXL1, BCOR, IDH1/2, RUNX1, SRSF2, TET2, TP53; complex karyotype and cytogenetically normal AML (CN-AML)]; group 2 with decreasing frequency with increasing age (CEBPA, EZH2, FLT3-TKD, GATA2, KIT, KRAS, PTPN11, NRAS, WT1; inv(16), t(8;21) and 11q23/KMT2A rearrangements) and group 3 with non-linear frequency distribution, which included the 3 most common AML-associated gene mutations (NPM1, DNMT3A, FLT3-ITD), SF3B1 and mutations in the cohesin complex genes (RAD21, SMC1A, SMC3, STAG2) (Fig. 1A). Notably, within the first 2 distribution groups, there seem to be no obvious age that could serve as a cut point separating age groups that are markedly different with regard to their molecular patterns. Particularly, this includes an age group that is commonly used for pt cohort definitions such as pts aged 18-39 y referred to as adolescent and young adults (AYA) or even treatment decisions and eligibility (eg, ages 60 or 65 and older for consideration as elderly AML). With respect to pt outcomes, expectedly, there was almost linear shortening of overall survival (OS) as age increased (p Conclusions: To our knowledge, this is the first large scale depiction of mutational patterns in AML inclusive of the entire adult age spectrum. Our international study demonstrates that patterns of individual mutations based on age are remarkably consistent between countries, and defy assortment based on typical age conventions. Given the continuous distribution of either increasing or decreasing frequency of many mutations, there are distinctly different mutational profiles for the youngest pts compared with older pts, however choosing a precise cut-off, such as age 39 for AYA pts or 59 for consideration as "younger AML", does not seem to be supported by our analyses. This observation supports a more personalized approach that also considers molecular subgroups in clinical practice instead of the age rigidity set in many clinical trials. *shared first: M.C.,K.L.; #last: T.H.,AK.E. Figure 1 Figure 1. Disclosures Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Mims: Glycomemetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Aptevo: Research Funding; Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Xencor: Research Funding; Kartos Pharmaceuticals: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Walker: Karyopharm Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Blum: Celyad Oncology: Research Funding; Forma Therapeutics: Research Funding; Xencor: Research Funding; Nkarta: Research Funding; Leukemia and Lymphoma Society: Research Funding; Abbvie: Honoraria; AmerisourceBergen: Honoraria; Syndax: Honoraria. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Stone: Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Innate: Consultancy; GlaxoSmithKline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Metzeler: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Honoraria; Astellas: Honoraria; AbbVie: Honoraria; Pfizer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding. Eisfeld: Karyopharm (spouse): Current Employment.
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- 2021
20. PTPN11 mutations and Outcomes in Adult Patients with Acute Myeloid Leukemia
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Annika Dufour, Tobias Herold, Dennis Görlich, Jan Braess, Bernhard Wörmann, Klaus H. Metzeler, Stephanie Schneider, Maja Rothenberg-Thurley, Karsten Spiekermann, Utz Krug, Maria Cristina Sauerland, Wolfgang Hiddemann, Marion Subklewe, and Wolfgang E. Berdel
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Oncology ,medicine.medical_specialty ,NPM1 ,business.industry ,Immunology ,Hazard ratio ,Induction chemotherapy ,Myeloid leukemia ,Cell Biology ,Hematology ,Gene mutation ,medicine.disease ,Biochemistry ,PTPN11 ,Leukemia ,Internal medicine ,medicine ,Cytarabine ,business ,medicine.drug - Abstract
Background: Mutations in the protein tyrosine phosphatase gene PTPN11 (also known as SHP2) are found in approximately 10% of adult patients with acute myeloid leukemia (AML). A recent study reported that mutated PTPN11 associates with inferior response rates and shorter survival among intensively treated AML patients, independently of the ELN prognostic groups (Alfayez et al., Leukemia 2020). Earlier analyses of the genomic landscape of AML did not uncover a similar prognostic relevance of PTPN11 mutations. Therefore, our aim was to clarify the prognostic relevance of mutated PTPN11 variants in AML patients receiving intensive front-line therapy. Patients and Methods: We studied 1116 AML patients enrolled on two subsequent multicenter phase III trials of the German AML Cooperative Group (AML-CG 1999, NCT00266136; and AML-CG 2008, NCT01382147) who were genetically characterized by amplicon-based targeted next-generation sequencing (Herold et al., Leukemia 2020). All patients had received induction chemotherapy containing cytarabine and daunorubicin or mitoxantrone. Results: We identified 146 PTPN11 mutations in 114 of 1116 patients (10%). Mutations clustered in two hotspot regions (5': codons 52-79; n=108 and 3': codons 491-512, n=38) as previously reported. Associations of PTPN11 mutations with baseline clinical and genetic patient characteristics are shown in Figure A. PTPN11 mutations were most frequent in the European LeukemiaNet (ELN) "favorable" genetic risk group, and associated with higher leukocyte counts. Patients with mutated PTPN11more commonly had mutated NPM1, IDH1 and DNMT3A, and less frequently had FLT3-ITD, IDH2 and TP53 mutations, compared to patients with wild-type PTPN11. With regard to treatment outcomes, the rate of complete remission was similar among patients with mutated and wild-type PTPN11 (65% vs. 59%, P=.25). In univariate analyses, PTPN11-mutated patients had significantly longer relapse-free survival (RFS; 5-year estimate, 55% vs 33% for PTPN11-wild type patients; P=.001; Figure B) and tended to have longer overall survival (OS; 5-year estimate, 43% vs 32%; P=.06; Figure C). However, in multivariable models adjusting for age, sex, leukocyte count, AML type (de novo/sAML/tAML) and ELN-2017 genetic risk group, mutated PTPN11 no longer associated with RFS (hazard ratio [HR], 0.89, 95% confidence interval [CI], 0.63 - 1.27; P=0.53) or OS (HR, 1.03; 95% CI, 0.80 - 1.33; P=.79). Moreover, PTPN11 mutations did not significantly associate with RFS or OS within any of the ELN genetic risk groups. Finally, we detected no significant differences in baseline characteristics or outcomes between patients with PTPN11 mutations affecting the 5' hotspot region (n=82), the 3' hotspot region (n=21), or mutations at both hotspots (n=11). Conclusion: In our cohort of newly diagnosed and intensively treated AML patients, mutations in PTPN11 occurred in 10% and associated with prognostically favorable genetic characteristics such as mutated NPM1 and absence of FLT3-ITD and TP53mutations. Consequently, PTPN11 mutations were most commonly found within the ELN-2017 favorable risk category. While patients with PTPN11 mutations had relatively favorable survival outcomes, multivariable models suggest this observation is confounded by the frequent co-occurrence of known favorable genetic markers. Our data are in disagreement with a recently published study on 880 newly diagnosed patients that found an unfavourable prognostic impact of mutated PTPN11, particularly among the 410 patients who received intensive treatment. Possible explanations for these discrepant results include differences in treatment regimens between the two cohorts, as well as the play of chance when studying a relatively rare gene mutation in medium-sized cohorts. In summary, our data do not support a role of PTPN11 mutations as an adverse prognostic biomarker in newly diagnosed, intensively treated adult AML patients. Figure Disclosures Metzeler: Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Honoraria. Subklewe:AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Morphosys: Research Funding; Seattle Genetics: Research Funding; Roche AG: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding.
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- 2020
21. Acute myeloid leukemia with del(9q) is characterized by frequent mutations ofNPM1,DNMT3A, WT1and low expression ofTLE4
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Wolfgang Hiddemann, Stephanie Schneider, Alexander Graf, Sebastian Vosberg, Sabrina Opatz, Helmut Blum, Klaus H. Metzeler, Philipp A. Greif, Tobias Herold, Evelyn Zellmeier, Bernhard Wörmann, Karsten Spiekermann, Stefan Krebs, Nikola P. Konstandin, Luise Hartmann, Bianka Ksienzyk, Vindi Jurinovic, Maria Cristina Sauerland, Ulrich Mansmann, Wolfgang E. Berdel, Thomas Büchner, and Stefan K. Bohlander
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0301 basic medicine ,Genetics ,Cancer Research ,NPM1 ,Myeloid leukemia ,Karyotype ,Chromosome 9 ,Biology ,Genetic analysis ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,Gene ,Exome sequencing - 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
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- 2016
22. Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification
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Diego Chacon, Maria Cristina Sauerland, Shruthi Subramanian, John E. Pimanda, Bernhard Wörmann, Bogdan Gabrys, Tobias Herold, Wolfgang Hiddemann, Ali Braytee, Wolfgang E. Berdel, Dominik Beck, Stefan K. Bohlander, Klaus H. Metzeler, Jan Braess, Yizhou Huang, and Julie A. I. Thoms
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Oncology ,medicine.medical_specialty ,Training set ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Gene Component ,Biochemistry ,Chemotherapy regimen ,Risk groups ,Internal medicine ,Risk stratification ,medicine ,Routine clinical practice ,Genetic risk ,business - Abstract
Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal component analysis of the gene components from the eight tested PGES). These patients shared intrinsic and measurable transcriptome characteristics (Figure 1C: Hierarchical cluster analysis of the differentially expressed genes) and could be prospectively identified using a high-fidelity prediction algorithm (FPA). In the training set (i.e. from the HOVON), the FPA achieved an accuracy of ~80% (10-fold cross-validation) and an AUC of 0.79 (receiver-operating characteristics). High-fidelity patients were dichotomized into adverse- or favorable- risk groups with significant differences in overall survival (OS) by all eight PGES (Figure 1D) and low-fidelity patients by two of the eight PGES (Figure 1E). In the three independent test sets (i.e. form the TCGA and AMLCG), patients with predicted high-fidelity were consistently dichotomized into the same adverse- or favorable- risk groups with significant differences in OS by all eight PGES. However, in-line with our previous analysis, patients with predicted low-fidelity were dichotomized into opposing adverse- or favorable- risk groups by the eight tested PGES. Conclusion: With appropriate patient selection, existing PGES improve outcome predictions and could guide treatment recommendations for patients without accurate genetic risk predictions (~18-25%) and for those with intermediate genetic risk (~32-35%). Figure 1 Disclosures Hiddemann: Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Metzeler:Celgene: Honoraria, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Honoraria. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beck:Gilead: Research Funding.
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- 2019
23. 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
24. Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet
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Francesco Lo-Coco, Maria-Cristina Sauerland, Massimo Breccia, Sebastian Lehmann, Maria Pagoni, A. M. Nloga, Pau Montesinos, Bhuvan Kishore, Wolf-K. Hofmann, Lionel Adès, Safaa M. Ramadan, Anne Schmidt, E. Di Bona, Jean-Francois Lambert, David Grimwade, Jose D. González-Sanmiguel, Pierre Fenaux, A. J G Huerta, Eva Lengfelder, Miguel A. Sanz, Dennis Görlich, and Bruno Cassinat
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Male ,Cancer Research ,International Cooperation ,Gastroenterology ,Arsenicals ,European LeukemiaNet ,chemistry.chemical_compound ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Recurrence ,80 and over ,Cumulative incidence ,Prospective Studies ,Registries ,Leukocytosis ,Arsenic trioxide ,Child ,Aged, 80 and over ,Promyelocytic ,Leukemia ,Cell Differentiation ,Oxides ,Hematology ,Middle Aged ,Europe ,Treatment Outcome ,Oncology ,Child, Preschool ,Female ,medicine.symptom ,Adult ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Adolescent ,Antineoplastic Agents ,Acute ,Disease-Free Survival ,Young Adult ,Internal medicine ,medicine ,Humans ,Autologous transplantation ,Preschool ,Aged ,business.industry ,medicine.disease ,Surgery ,Transplantation ,chemistry ,business ,Settore MED/15 - Malattie del Sangue - Abstract
In 2008, a European registry of relapsed acute promyelocytic leukemia was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (P=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the 3-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90 and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in second CR (n=93), the 3-year OS was 80% compared with 59% without transplantation (n=55) (P=0.03). Multivariable analysis demonstrated the favorable prognostic impact of first remission duration ⩾1.5 years, achievement of mCR and allogeneic or autologous transplantation on OS of patients alive after induction (P=0.03, P=0.01, P=0.01) and on leukemia-free survival (P=0.006, P
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- 2015
25. Impact of multiplex PCR on antimicrobial treatment in febrile neutropenia: a randomized controlled study
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Evgeny A, Idelevich, Gerda, Silling, Yvonne, Niederbracht, Hanna, Penner, Maria Cristina, Sauerland, Sascha, Tafelski, Irit, Nachtigall, Wolfgang E, Berdel, Georg, Peters, Karsten, Becker, and M, Wilke
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Adult ,Male ,Microbiology (medical) ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Immunology ,law.invention ,Sepsis ,Medical microbiology ,Anti-Infective Agents ,Randomized controlled trial ,law ,Internal medicine ,Multiplex polymerase chain reaction ,medicine ,Humans ,Immunology and Allergy ,Blood culture ,Aged ,Febrile Neutropenia ,medicine.diagnostic_test ,business.industry ,General Medicine ,Middle Aged ,Antimicrobial ,medicine.disease ,Surgery ,Treatment Outcome ,Molecular Diagnostic Techniques ,Hematologic Neoplasms ,Female ,business ,Multiplex Polymerase Chain Reaction ,Febrile neutropenia ,Central venous catheter - Abstract
Multiplex PCR (mPCR) directly from blood has been suggested as a promising method for rapid identification of pathogens causing sepsis. This study aimed to investigate whether mPCR has any impact on antimicrobial treatment. Hematological patients with febrile neutropenia were randomized into two groups. In the study group, mPCR was performed as an addition to standard diagnostics, and PCR finding was immediately communicated to the clinicians, thus being available for decision making. In the control group, clinicians were not aware of PCR result. PCR samples were collected simultaneously with clinically indicated blood culture specimens from peripheral vein and/or central venous catheter at fever onset and once again if fever persisted up to 72 h. Overall, 74 patients of the study group and 76 patients of the control group were enrolled and 253 samples collected. Therapy was changed to targeted antimicrobial therapy (AMT) in 12 patients (16.2 %) in the study group and in 12 patients (15.8 %) in the control group. For patients with changes, the median time to change to the targeted AMT was 21.4 h in the study group and 47.5 h in the control group (p = 0.018). In the study group, 57.1 % (8/14) of changes to targeted AMT was due to PCR finding. PCR led to AMT change in 9.5 % (7/74) of study group patients, i.e., in 33.3 % (7/21) of patients who had positive PCR finding. There were no significant differences in patient outcomes (secondary endpoints). In conclusion, PCR method accelerates change to the targeted AMT in febrile neutropenic patients.
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- 2015
26. Multiplex PCR assay underreports true bloodstream infections with coagulase-negative staphylococci in hematological patients with febrile neutropenia
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Wolfgang E. Berdel, Irit Nachtigall, Gerda Silling, Sascha Tafelski, Yvonne Reers, Maria Cristina Sauerland, Georg Peters, Karsten Becker, Evgeny A. Idelevich, and Hanna Pätkau
- Subjects
Adult ,Coagulase ,0301 basic medicine ,Microbiology (medical) ,Staphylococcus ,030106 microbiology ,Hematologic Neoplasms ,Biology ,Staphylococcal infections ,medicine.disease_cause ,Sensitivity and Specificity ,Sepsis ,03 medical and health sciences ,Multiplex polymerase chain reaction ,medicine ,Humans ,Febrile Neutropenia ,Bacteriological Techniques ,General Medicine ,Staphylococcal Infections ,medicine.disease ,Antimicrobial ,Infectious Diseases ,Molecular Diagnostic Techniques ,Immunology ,Multiplex Polymerase Chain Reaction ,Febrile neutropenia - Abstract
SeptiFast multiplex PCR assay was evaluated for detecting true bloodstream infections (BSIs) with coagulase-negative staphylococci (CoNS) in neutropenic hematological patients. Sensitivity for samples representing true CoNS-BSIs was 23.3% with an integrated cutoff and increased to 83.3% if the cutoff was neglected. Hence, the cutoff may prohibit timely targeted antimicrobial therapy.
- Published
- 2016
27. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia
- Author
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Wolfgang Hiddemann, Maja Rothenberg-Thurley, Susanne Amler, Stefan K. Bohlander, Stephanie Schneider, Max Hubmann, Karsten Spiekermann, Bianka Ksienzyk, Maria Cristina Sauerland, Jan Braess, Klaus H. Metzeler, Andreas Faldum, Tobias Herold, Dennis Goerlich, Nikola P. Konstandin, Thomas Köhnke, Marion Subklewe, and Evelyn Zellmeier
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Allogeneic transplantation ,Myeloid ,Neoplasm, Residual ,Risk Assessment ,Article ,DNA Methyltransferase 3A ,Clonal Evolution ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Bone Marrow ,Recurrence ,Internal medicine ,Biomarkers, Tumor ,Medicine ,Humans ,Cumulative incidence ,DNA (Cytosine-5-)-Methyltransferases ,Risk factor ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,business.industry ,Hazard ratio ,Remission Induction ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Transplantation ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Mutation ,Female ,business ,Biomarkers - Abstract
Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a VAF of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p
- Published
- 2017
28. Acute myeloid leukemia with del(9q) is characterized by frequent mutations of NPM1, DNMT3A, WT1 and low expression of TLE4
- Author
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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
- Subjects
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
29. PF210 CLINICAL ASPECTS AND DIFFERENTIAL SPLICING IN ACUTE MYELOID LEUKEMIA PATIENTS WITH SRSF2, U2AF1 AND SF3B1 MUTATIONS
- Author
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Tobias Herold, Maja Rothenberg-Thurley, Ulrich Mansmann, Aarif M. N. Batcha, Wolfgang E. Berdel, Maria Cristina Sauerland, Wolfgang Hiddemann, Stephanie Schneider, Stefan K. Bohlander, Hanna Janke, Jan Braess, Stefan Krebs, Helmut Blum, Julia Philippou-Massier, Bianka Ksienzyk, Stefanos A. Bamopoulos, Dennis Görlich, Karsten Spiekermann, Bernhard J. Woermann, Klaus H. Metzeler, Nikola P. Konstandin, and Vindi Jurinovic
- Subjects
business.industry ,RNA splicing ,Cancer research ,Myeloid leukemia ,Medicine ,Hematology ,business ,Differential (mathematics) - Published
- 2019
30. Identification of a 24-Gene Prognostic Signature That Improves the European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: An International Collaborative Study
- Author
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Michael A. Caligiuri, Bob Löwenberg, Xinan Yang, Stefan K. Bohlander, Tobias Herold, Zejuan Li, Jianjun Chen, Ulrich Mansmann, Kati Maharry, Paul P. Liu, Mary Beth Neilly, Michael D. Radmacher, Konstanze Döhner, Yanming Zhang, Guido Marcucci, Peter J. M. Valk, Maria Cristina Sauerland, Janet D. Rowley, Clara D. Bloomfield, Ruud Delwel, Thomas Büchner, Richard A. Larson, Xi Jiang, Lars Bullinger, Michelle M. Le Beau, Vindi Jurinovic, Ping Chen, Miao Sun, Hao Huang, Wolfgang Hiddemann, Chunjiang He, Abdel G. Elkahloun, Hematology, and Rehabilitation Medicine
- Subjects
Cancer Research ,Myeloid ,International Cooperation ,Kaplan-Meier Estimate ,Bioinformatics ,European LeukemiaNet ,Humans ,Medicine ,Proportional Hazards Models ,Microarray analysis techniques ,business.industry ,Proportional hazards model ,Gene Expression Profiling ,Myeloid leukemia ,ORIGINAL REPORTS ,Middle Aged ,Microarray Analysis ,Prognosis ,medicine.disease ,Gene expression profiling ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Oncology ,Meta-analysis ,business - Abstract
Purpose To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification. Patients and Methods Four independent sets totaling 499 patients with AML carrying various cytogenetic and molecular abnormalities were used as training sets. Two independent patient sets composed of 825 patients were used as validation sets. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses. Results A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS. Conclusion Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification.
- Published
- 2013
31. Acute Myeloid Leukemia (AML): Different Treatment Strategies Versus a Common Standard Arm—Combined Prospective Analysis by the German AML Intergroup
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Achim Heinecke, Markus Pfirrmann, R.F. Schlenk, Verena S. Hoffmann, Joerg Hasford, Wolfgang Hiddemann, Michael Kramer, Hartmut Döhner, Markus Schaich, Maria Cristina Sauerland, Dietger Niederwieser, Utz Krug, Rainer Krahl, Konstanze Döhner, Daniela Späth, Jürgen Krauter, Dieter Hoelzer, Rüdiger Hehlmann, Arnold Ganser, Thomas Büchner, Gerhard Ehninger, Sebastian Scholl, Gerhard Heil, and Wolfgang E. Berdel
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Randomization ,Adolescent ,Kaplan-Meier Estimate ,Gene mutation ,Risk Assessment ,Severity of Illness Index ,Disease-Free Survival ,Drug Administration Schedule ,law.invention ,Young Adult ,Sex Factors ,Randomized controlled trial ,law ,Germany ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Confidence Intervals ,medicine ,Humans ,Prospective Studies ,Infusions, Intravenous ,Prospective cohort study ,Proportional Hazards Models ,Dose-Response Relationship, Drug ,business.industry ,Daunorubicin ,Age Factors ,Cytarabine ,Myeloid leukemia ,Middle Aged ,Prognosis ,Survival Analysis ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Purpose Identifying true therapeutic progress in patients with acute myeloid leukemia (AML) requires a comparison of treatment strategies and results on the basis of uniform patient selection. To foster comparability across five clinical studies, we introduced a common standard arm combined with a general upfront randomization and performed prospective analyses with adjustment for differences in prognostic baseline characteristics. Patients and Methods Whereas the studies' own regimens differed in chemotherapies, risk adaption, and guidelines for allogeneic stem-cell transplantation, the standard arm contained uniform cytarabine- and anthracycline-based standard-dose remission induction and high-dose consolidation courses. Results Of 2,995 evaluable patients aged 16 to 60 years, 290 patients were randomly assigned to the common standard arm. Seventy percent of the 290 achieved complete remissions (62% with complete recovery, 8% with incomplete recovery; 95% CI, 65% to 76%). Five-year survival probabilities were 44.3% (95% CI, 37.7% to 50.7%) for overall survival, 44.8% (95% CI, 37.0% to 52.2%) for relapse-free survival, and 31.5% (95% CI, 25.7% to 37.4%) for event-free survival. Neither the unadjusted survival probabilities of the Kaplan-Meier method nor their adjustment for prognostic variables in multiple Cox regression models led to statistically significant different results in the three survival end points when the outcomes of each study were compared with the standard arm. Conclusion A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared through a common standard treatment arm. The results provide a representative basis for further therapeutic approaches.
- Published
- 2012
32. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation
- Author
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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
- Subjects
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
33. Age, not therapy intensity, determines outcomes of adults with acute myeloid leukemia
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R Peter Gale, Torsten Haferlach, Peter Staib, Eva Lengfelder, Rolf M. Mesters, Wolfgang E. Berdel, Aristoteles Giagounidis, Utz Krug, Ruediger Hehlmann, Th. Büchner, A. Reichle, K. Spiekermann, Hubert Serve, Leopold Balleisen, Bernhard Wörmann, Andreas Grüneisen, Dennis Görlich, M Stelljes, Jan Braess, Maria-Cristina Sauerland, Andreas Faldum, Wolfgang Hiddemann, Wolfgang Köpcke, Susanne Schnittger, Hartmut Eimermacher, Carsten Müller-Tidow, Herbert Rasche, Achim Heinecke, and Claudia Haferlach
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Treatment outcome ,Kaplan-Meier Estimate ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Young adult ,Aged ,Aged, 80 and over ,business.industry ,Age Factors ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,Intensity (physics) ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunology ,Female ,business ,030215 immunology - Published
- 2016
34. A 4-gene expression score associated with high levels of Wilms Tumor-1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia
- Author
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Peter J. M. Valk, Stefan K. Bohlander, Dominique Bonnet, Tobias Herold, Thomas Buchner, Wolfgang Hiddemann, Ahmadreza Niavarani, Maria Cristina Sauerland, Yasmin Reyal, and Hematology
- Subjects
0301 basic medicine ,Adult ,Genetic Markers ,Genes, Wilms Tumor ,Value (computer science) ,Kaplan-Meier Estimate ,Biology ,urologic and male genital diseases ,gene signature ,03 medical and health sciences ,0302 clinical medicine ,AML ,hemic and lymphatic diseases ,Gene expression ,medicine ,Biomarkers, Tumor ,Humans ,WT1 Proteins ,Gene ,Surrogate endpoint ,Haematological Malignancy ,urogenital system ,Gene Expression Profiling ,Wilms' tumor ,Hematology ,Gene signature ,Middle Aged ,medicine.disease ,Prognosis ,female genital diseases and pregnancy complications ,WT1 ,Gene expression profiling ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Genetic marker ,030220 oncology & carcinogenesis ,Cancer research ,expression score ,Research Paper - Abstract
Summary Wilms Tumor‐1 (WT1) expression level is implicated in the prognosis of acute myeloid leukaemia (AML). We hypothesized that a gene expression profile associated with WT1 expression levels might be a good surrogate marker. We identified high WT1 gene sets by comparing the gene expression profiles in the highest and lowest quartiles of WT1 expression in two large AML studies. Two high WT1 gene sets were found to be highly correlated in terms of the altered genes and expression profiles. We identified a 17‐probe set signature of the high WT1 set as the optimal prognostic predictor in the first AML set, and showed that it was able to predict prognosis in the second AML series after adjustment for European LeukaemiaNet genetic groups. The gene signature also proved to be of prognostic value in a third AML series of 163 samples assessed by RNA sequencing, demonstrating its cross‐platform consistency. This led us to derive a 4‐gene expression score, which faithfully predicted adverse outcome. In conclusion, a short gene signature associated with high WT1 expression levels and the resultant 4‐gene expression score were found to be predictive of adverse prognosis in AML. This study provides new clues to the molecular pathways underlying high WT1 states in leukaemia.
- Published
- 2016
35. Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia
- Author
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Georg Maschmeyer, W.-D. Ludwig, Hubert Serve, Leopold Balleisen, Peter Staib, Wolfgang E. Berdel, Christoph Schliemann, Karsten Spiekermann, Eckhard Thiel, Bernhard Wörmann, Th. Büchner, M Stelljes, Dennis Görlich, Carsten Müller-Tidow, Wolfgang Köpcke, Achim Heinecke, Susanne Schnittger, Aristoteles Giagounidis, Claudia Haferlach, Jan Braess, Andreas Grüneisen, Maria-Cristina Sauerland, Hartmut Eimermacher, Herbert Rasche, Wolfgang Kern, Robert Peter Gale, Wolfgang Hiddemann, Dietrich W. Beelen, A. Reichle, Carlo Aul, Ruediger Hehlmann, Utz Krug, Torsten Haferlach, and Eva Lengfelder
- Subjects
Adult ,Cancer Research ,medicine.medical_specialty ,Medizin ,Transplantation, Autologous ,Disease-Free Survival ,law.invention ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Maintenance therapy ,Randomized controlled trial ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,Survival rate ,Mitoxantrone ,business.industry ,Danazol ,Cytarabine ,Induction chemotherapy ,Hematology ,Induction Chemotherapy ,Middle Aged ,Aminoglutethimide ,Confidence interval ,Surgery ,Transplantation ,Survival Rate ,Leukemia, Myeloid, Acute ,Tamoxifen ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug ,Stem Cell Transplantation - Abstract
We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects
- Published
- 2015
36. Allogeneic transplantation as post-remission therapy for cytogenetically high-risk acute myeloid leukemia: landmark analysis from a single prospective multicenter trial
- Author
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Achim Heinecke, Dietrich W. Beelen, Wolfgang Hiddemann, Hubert Serve, Maria Cristina Sauerland, Matthias Stelljes, Hans J. Kolb, Renate Arnold, Joachim Kienast, Karsten Spiekermann, Ernst Holler, Carsten Müller-Tidow, Wolfgang E. Berdel, Bjorna Berning, Gerda Silling, Jan Braess, Rainer Schwerdtfeger, and Thomas Büchner
- Subjects
Adult ,Male ,medicine.medical_specialty ,Allogeneic transplantation ,medicine.medical_treatment ,Population ,Medizin ,Hematopoietic stem cell transplantation ,Cytogenetics ,Young Adult ,Monosomy ,Recurrence ,Internal medicine ,Multicenter trial ,medicine ,Humans ,Transplantation, Homologous ,education ,Survival analysis ,Neoadjuvant therapy ,education.field_of_study ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Original Articles ,Hematology ,Middle Aged ,Survival Analysis ,Neoadjuvant Therapy ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Female ,business - Abstract
Background Allogeneic hematopoietic cell transplantation is considered the preferred post-remission therapy in patients with acute myeloid leukemia cytogenetically defined as being at high risk. To substantiate evidence for allogeneic hematopoietic cell transplantation in first complete remission in these high-risk patients we performed a landmark analysis within a single prospective multicenter treatment trial.By the time of analysis, 2,347 patients had been accrued into the AMLCG 99 trial between 1999 - 2007. Out of this population, 243 patients under 60 years old fulfilled the criteria for high-risk cytogenetics. Landmark analyses were performed with a control cohort, who remained in first complete remission at least the median time from complete remission to transplantation in the intervention group.After standardized induction therapy, 111 patients under 60 years old achieved complete remission. A matched allogeneic donor was identified for 59 patients (30 sibling donors, 29 unrelated donors). Fifty-five patients received an allogeneic hematopoietic cell transplant after a median time of 88 days in first complete remission. Of the remaining 56 patients, 21 relapsed within 90 days after achieving first complete remission and for 7 patients with relevant comorbidities no donors search was initiated, leaving 28 patients given conventional post-remission therapy as the control cohort. The median follow-up of surviving patients was 60.4 months. Patients with an allogeneic donor had substantially better 5-year overall and relapse-free survival rates than the control group (48% versus 18%, P=0.004 and 39% versus 10%, P0.001, respectively). A survival benefit from transplantation was evident regardless of donor type, age and monosomal karyotype. Conclusions Beyond evidence available for subgroups of high-risk patients, the findings of this study establish in a broader manner that allogeneic hematopoietic cell transplantation is a preferable consolidation treatment for patients with acute myeloid leukemia and high-risk cytogenetics. The study was registered at Clinicaltrials.gov as NCT00266136.
- Published
- 2011
37. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes
- Author
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Utz, Krug, Christoph, Röllig, Anja, Koschmieder, Achim, Heinecke, Maria Cristina, Sauerland, Markus, Schaich, Christian, Thiede, Michael, Kramer, Jan, Braess, Karsten, Spiekermann, Torsten, Haferlach, Claudia, Haferlach, Steffen, Koschmieder, Christian, Rohde, Hubert, Serve, Bernhard, Wörmann, Wolfgang, Hiddemann, Gerhard, Ehninger, Wolfgang E, Berdel, Thomas, Büchner, Carsten, Müller-Tidow, and W, Zschille
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Myeloid ,medicine.medical_treatment ,Risk Assessment ,Tioguanine ,Predictive Value of Tests ,Risk Factors ,Germany ,Surveys and Questionnaires ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged ,Aged, 80 and over ,Internet ,Mitoxantrone ,Chemotherapy ,business.industry ,Daunorubicin ,Remission Induction ,Cytarabine ,Induction chemotherapy ,General Medicine ,Middle Aged ,Prognosis ,Surgery ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Predictive value of tests ,Multivariate Analysis ,Cohort ,Regression Analysis ,Female ,business ,medicine.drug - Abstract
Summary Background About 50% of patients (age ≥60 years) who have acute myeloid leukaemia and are otherwise medically healthy (ie, able to undergo intensive chemotherapy) achieve a complete remission (CR) after intensive chemotherapy, but with a substantially increased risk of early death (ED) compared with younger patients. We verified the association of standard clinical and laboratory variables with CR and ED and developed a web-based application for risk assessment of intensive chemotherapy in these patients. Methods Multivariate regression analysis was used to develop risk scores with or without knowledge of the cytogenetic and molecular risk profiles for a cohort of 1406 patients (aged ≥60 years) with acute myeloid leukaemia, but otherwise medically healthy, who were treated with two courses of intensive induction chemotherapy (tioguanine, standard-dose cytarabine, and daunorubicin followed by high-dose cytarabine and mitoxantrone; or with high-dose cytarabine and mitoxantrone in the first and second induction courses) in the German Acute Myeloid Leukaemia Cooperative Group 1999 study. Risk prediction was validated in an independent cohort of 801 patients (aged >60 years) with acute myeloid leukaemia who were given two courses of cytarabine and daunorubicin in the Acute Myeloid Leukaemia 1996 study. Findings Body temperature, age, de-novo leukaemia versus leukaemia secondary to cytotoxic treatment or an antecedent haematological disease, haemoglobin, platelet count, fibrinogen, and serum concentration of lactate dehydrogenase were significantly associated with CR or ED. The probability of CR with knowledge of cytogenetic and molecular risk (score 1) was from 12% to 91%, and without knowledge (score 2) from 21% to 80%. The predicted risk of ED was from 6% to 69% for score 1 and from 7% to 63% for score 2. The predictive power of the risk scores was confirmed in the independent patient cohort (CR score 1, from 10% to 91%; CR score 2, from 16% to 80%; ED score 1, from 6% to 69%; and ED score 2, from 7% to 61%). Interpretation The scores for acute myeloid leukaemia can be used to predict the probability of CR and the risk of ED in older patients with acute myeloid leukaemia, but otherwise medically healthy, for whom intensive induction chemotherapy is planned. This information can help physicians with difficult decisions for treatment of these patients. Funding Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft.
- Published
- 2010
38. Acute Myeloid Leukemia With Biallelic CEBPA Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated With a Favorable Clinical Outcome
- Author
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Wolfgang Hiddemann, Tobias Benthaus, Thomas Büchner, Stephanie Schneider, Bernhard Wörmann, Eva Hoster, Jan Braess, Annika Dufour, Wolfgang E. Berdel, Maria-Cristina Sauerland, Evelyn Zellmeier, Stefan K. Bohlander, Friederike Schneider, Karsten Spiekermann, and Klaus H. Metzeler
- Subjects
Adult ,Male ,Cancer Research ,NPM1 ,Myeloid ,Adolescent ,medicine.disease_cause ,Young Adult ,CEBPA ,Biomarkers, Tumor ,medicine ,Humans ,Survival rate ,Alleles ,Aged ,Neoplasm Staging ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,Mutation ,Gene Expression Regulation, Leukemic ,business.industry ,Gene Expression Profiling ,Nuclear Proteins ,Myeloid leukemia ,MINIMAL RESIDUAL DISEASE ,BINDING-PROTEIN-ALPHA ,C/EBP-ALPHA ,PROGNOSTIC-SIGNIFICANCE ,EXPRESSION PROFILE ,TANDEM DUPLICATION ,RELAPSE SAMPLES ,AML ,FLT3 ,CYTOGENETICS ,Histone-Lysine N-Methyltransferase ,Middle Aged ,Prognosis ,medicine.disease ,Survival Rate ,Gene expression profiling ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,Oncology ,Karyotyping ,CCAAT-Enhancer-Binding Proteins ,Cancer research ,Female ,business ,Nucleophosmin ,Myeloid-Lymphoid Leukemia Protein - Abstract
Purpose CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML). Patients and Methods Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we obtained gene expression profiles using oligonucleotide microarrays. Results Only patients with biCEBPA had an improved median overall survival when compared with patients with wtCEBPA (not reached v 20.4 months, respectively; P = .018), whereas patients with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P = .506). Multivariable analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognostic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated with mutated NPM1 (0% v 43%, respectively; P < .001) and rarely associated with FLT3 internal tandem duplication (ITD; 5% v 23%, respectively; P = .059), whereas patients with moCEBPA had a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD compared with patients with wtCEBPA (44% v 23%, respectively; P = .037). Furthermore, patients with biCEBPA showed a homogeneous gene expression profile that was characterized by downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in their gene expression profiles. Conclusion Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a different frequency of associated gene mutations. These findings are of great significance for risk-adapted therapeutic strategies in AML.
- Published
- 2010
39. ERG Expression Is an Independent Prognostic Factor and Allows Refined Risk Stratification in Cytogenetically Normal Acute Myeloid Leukemia: A Comprehensive Analysis of ERG, MN1, and BAALC Transcript Levels Using Oligonucleotide Microarrays
- Author
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Wolfgang E. Berdel, Jan Braess, Christian Buske, Ulrich Mansmann, Klaus H. Metzeler, Maria-Cristina Sauerland, Achim Heinecke, Annika Dufour, Karsten Spiekermann, Bernhard Wörmann, Tobias Benthaus, Thomas Büchner, Wolfgang Hiddemann, Manuela Hummel, and Stefan K. Bohlander
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,NPM1 ,Myeloid ,Adolescent ,Transcription, Genetic ,Risk Assessment ,Cohort Studies ,Young Adult ,Transcriptional Regulator ERG ,Risk Factors ,Internal medicine ,CEBPA ,medicine ,Humans ,Survival analysis ,BAALC ,Aged ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,internal tandem duplications ,high-dose cytarabine ,ets-related gene ,group-b ,normal karyotype ,prolonged maintenance ,favorable prognosis ,microrna expression ,prostate-cancer ,cebpa mutations ,business.industry ,Gene Expression Profiling ,Tumor Suppressor Proteins ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Neoplasm Proteins ,Gene expression profiling ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Immunology ,Trans-Activators ,Female ,business ,Nucleophosmin - Abstract
Purpose Recently, several novel molecular prognostic markers were identified in cytogenetically normal acute myeloid leukemia (CN-AML). In addition to the well-known influence of FLT3, NPM1, and CEBPA mutations, high transcript levels of the ERG, BAALC, and MN1 genes have been associated with inferior outcomes, but the relative importance of these risk markers remains to be defined. Patients and Methods We analyzed ERG, BAALC, and MN1 expression levels in a cohort of 210 patients with CN-AML who received intensive chemotherapy. Expression levels of ERG, BAALC, and MN1 were determined in bone marrow samples by using oligonucleotide microarrays. Results High transcript levels of ERG, BAALC, and MN1 were predictors for inferior overall survival (OS) and a lower rate of complete remissions (CRs). There were significant positive correlations between the expression levels of all three genes. ERG expression levels predicted OS in elderly patients (ie, age 60 years or older) with CN-AML (P = .006) as well as in younger patients (P = .013). In multivariate analyses, high ERG expression was independently associated with a lower CR rate (P = .013), shorter event-free survival (P = .008), and shorter OS (P = .005). Patients who had low ERG levels and absent FLT3 internal tandem duplication (ITD) had a 5-year OS of 44%, and patients who had high ERG expression and FLT3 ITD had a 5-year OS of only 5%. Conclusion We analyzed a comprehensive set of molecular risk factors in a large, homogeneous CN-AML patient cohort. In this study, high ERG expression levels emerged as a strong negative prognostic factor and provided prognostic information in addition to established molecular markers.
- Published
- 2009
40. NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS)
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Wolfgang Hiddemann, Bernhard J. Woermann, Eva Hoster, Christian Buske, Tobias Benthaus, Stephanie Schneider, Karsten Spiekermann, Thomas Buechner, Achim Heinecke, Maria Cristina Sauerland, Friederike Schneider, Michaela Feuring-Buske, Stefan K. Bohlander, Wolfgang E. Berdel, Susanne Fritsch, Jan Braess, Evelin Zellmeier, Gudrun Mellert, Michael Unterhalt, and Annika Dufour
- Subjects
Oncology ,medicine.medical_specialty ,NPM1 ,Myeloid ,Immunology ,Antineoplastic Agents ,Biology ,medicine.disease_cause ,Biochemistry ,hemic and lymphatic diseases ,Internal medicine ,Precursor cell ,medicine ,Humans ,Mutation ,Inverted Repeat Sequences ,Remission Induction ,Nuclear Proteins ,Myeloid leukemia ,Induction chemotherapy ,Cancer ,Cell Biology ,Hematology ,Prognosis ,medicine.disease ,Killer Cells, Natural ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,Karyotyping ,Myelodysplastic Syndromes ,Cancer research ,Blast Crisis ,Nucleophosmin - Abstract
Mutations in the NPM1 gene represent the most frequent genetic alterations in patients with acute myeloid leukemia (AML) and are associated with a favorable outcome. In 690 normal karyotype (NK) AML patients the complete remission rates (CRs) and the percentage of patients with adequate in vivo blast cell reduction 1 week after the end of the first induction cycle were significantly higher in NPM1+ (75% and 80%, respectively) than in NPM1− (57% and 57%, respectively) patients, but were unaffected by the FLT3-ITD status. Multivariate analyses revealed the presence of a NPM1 mutation as an independent positive prognostic factor for the achievement of an adequate day-16 blast clearance and a CR. In conclusion, NPM1+ blast cells show a high in vivo sensitivity toward induction chemotherapy irrespective of the FLT3-ITD mutation status. These findings provide insight into the pathophysiology and help to understand the favorable clinical outcome of patients with NPM1+ AML.
- Published
- 2009
41. Maintenance for Acute Myeloid Leukemia Revisited
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Utz Krug, Maria Cristina Sauerland, Wolfgang E. Berdel, Achim Heinecke, Wolfgang Hiddemann, Thomas Büchner, and Bernhard Wörmann
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medicine.medical_specialty ,Myeloid ,Randomization ,business.industry ,Mortality rate ,Myeloid leukemia ,Disease ,medicine.disease ,Surgery ,Leukemia, Myeloid, Acute ,Leukemia ,Regimen ,medicine.anatomical_structure ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Pharmacology (medical) ,In patient ,business ,Intensive care medicine - Abstract
Maintenance treatment for AML is an approach to minimize residual disease, optimize quality of remission and prevent a leukemic regrowth over a longer period of time. This intention implies a certain antileukemic activity and myelotoxicity. Thus, a prolonged myelosuppressive maintenance is best exemplified by the optimized protocol of the CALGB published by Kanti R. Rai in 1981 (Blood 58:1203-1212, 1981) and derived by the AMLCG as a therapeutic standard. From our today's knowledge about the impact of various strategies, a lack of postremission therapy is not compatible with durable remissions. Even after an induction-type consolidation, the classic CALGB-type maintenance, or a comparably intensive regimen improved the relapse-free survival over that from alternatives. Some studies which failed to show a benefit used maintenance at low-dosage or short duration. Data about maintenance delivery in patients reaching long-term remissions demonstrate feasibility and compliance, and a low maintenance-related death rate can compete with that from alternative options. Revisiting maintenance, however, requires a comparison with other strategies on the basis of intention-to-treat. Either single prospective trials or crosstrial networking by a common standard arm and general upfront randomization can further assess the relative value of maintenance for AML.
- Published
- 2007
42. Early assessment of minimal residual disease in aml by flow cytometry during aplasia identifies patients at increased risk of relapse
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Thomas Köhnke, Annika Dufour, Th. Büchner, Max Hubmann, Marion Subklewe, Laubender Rp, Maria-Cristina Sauerland, Stephanie Schneider, Jan Braess, Eva Hoster, Katharina Ringel, Wolfgang E. Berdel, Stefan K. Bohlander, Daniela Sauter, Karsten Spiekermann, Purvi M. Kakadia, Wolfgang Hiddemann, and Bernhard Wörmann
- Subjects
Male ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,medicine.medical_specialty ,Pathology ,Neoplasm, Residual ,Bone Marrow Cells ,Disease-Free Survival ,Flow cytometry ,Bone Marrow ,Risk Factors ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,neoplasms ,Aged ,Proportional Hazards Models ,medicine.diagnostic_test ,business.industry ,Remission Induction ,Nuclear Proteins ,Hematology ,Aplasia ,Middle Aged ,Flow Cytometry ,Prognosis ,medicine.disease ,Minimal residual disease ,body regions ,Leukemia, Myeloid, Acute ,stomatognathic diseases ,Treatment Outcome ,Increased risk ,Karyotyping ,Leukocytes, Mononuclear ,Female ,Neoplasm Recurrence, Local ,business ,Nucleophosmin - Abstract
In acute myeloid leukemia (AML), assessment of minimal residual disease (MRD) by flow cytometry (flow MRD) after induction and consolidation therapy has been shown to provide independent prognostic information. However, data on the value of earlier flow MRD assessment are lacking. Therefore, the value of flow MRD detection was determined during aplasia in 178 patients achieving complete remission after treatment according to AMLCG (AML Cooperative Group) induction protocols. Flow MRD positivity during aplasia predicted poor outcome (5-year relapse-free survival (RFS) 16% vs 43%, P0.001) independently from age and cytogenetic risk group (hazard ratio for MRD positivity 1.71; P=0.009). Importantly, the prognosis of patients without detectable MRD was neither impacted by morphological blast count during aplasia nor by MRD status postinduction. Early flow MRD was also evaluated in the context of existing risk factors. Flow MRD was prognostic within the intermediate cytogenetic risk group (5-year RFS 15% vs 37%, P=0.016) as well as for patients with normal karyotype and NPM1 mutations (5-year RFS 13% vs 49%, P=0.02) or FLT3-ITD (3-year RFS rates 9% vs 44%, P=0.016). Early flow MRD assessment can improve current risk stratification approaches by prediction of RFS in AML and might facilitate adaptation of postremission therapy for patients at high risk of relapse.
- Published
- 2015
43. Treatment of older patients with AML
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Maria Cristina Sauerland, Wolfgang E. Berdel, Achim Heinecke, Carlo Aul, Thomas Büchner, Rolf M. Mesters, Claudia Schoch, Hubert Serve, Joachim Kienast, Wolfgang Kern, Andreas Grüneisen, Leopold Balleisen, Herbert Rasche, Hartmut Eimermacher, Susanne Schnittger, Wolfgang Hiddemann, Albrecht Reichle, Bernhard Wörmann, Peter Staib, Andrea Schumacher, Torsten Haferlach, and Eva Lengfelder
- Subjects
Adult ,Oncology ,medicine.medical_specialty ,Allogeneic transplantation ,Daunorubicin ,medicine.medical_treatment ,Antineoplastic Agents ,Disease ,Targeted therapy ,Older patients ,Quality of life ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,Thioguanine ,Protein Kinase Inhibitors ,Aged ,Chemotherapy ,business.industry ,Remission Induction ,Therapeutic effect ,Age Factors ,Cytarabine ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,Surgery ,Leukemia, Myeloid, Acute ,business ,Stem Cell Transplantation ,medicine.drug - Abstract
Undertreatment of the older patients with AML can explain, in part, their inferior outcome when compared with that in younger patients. In analogy to the benefit of patients under the age of 60 years from high-dose AraC there are dosage related therapeutic effects in the patients over 60 years in particular for daunorubicin in the induction treatment, and for maintenance versus no maintenance in the post-remission treatment. Utilizing these effects can partly overcome the mostly unfavorable disease biology in older age AML, whereas the role of risk factors involved is not completely understood and the concept of dose–response needs to be requestioned. We recommend an adequate dosage of 60mg/(m 2 day) daunorubicin for 3 days in a combination with standard dose AraC and 6-thioguanine given for induction and consolidation and followed by a prolonged monthly maintenance chemotherapy. Further improvements in supportive care may help delivering additional anti-leukemic cytotoxicity. As a novel approach, reduced toxicity preparative regimens may open up allogeneic transplantation for older patients with AML. Other new options like MDR modulators, antibody targeted therapies and tyrosine kinase inhibitors are under clinical investigation. A questionnaire study in patients with AML showed that according to patients' self-assessment intensive and prolonged treatment did not result in decreasing quality of life. This finding did not vary by age under or above 60 years. Given the actual median age in this disease being more than 60 years the adequate management of older age AML remains as the major challenge.
- Published
- 2005
44. 6-Thioguanine, Cytarabine, and Daunorubicin (TAD) and High-Dose Cytarabine and Mitoxantrone (HAM) for Induction, TAD for Consolidation, and Either Prolonged Maintenance by Reduced Monthly TAD or TAD-HAM-TAD and One Course of Intensive Consolidation by Sequential HAM in Adult Patients at All Ages With De Novo Acute Myeloid Leukemia (AML): A Randomized Trial of the German AML Cooperative Group
- Author
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Rolf M. Mesters, Georg Maschmeyer, Helmut Löffler, Peter Staib, Bernhard Wörmann, Norbert Frickhofen, Claudia Schoch, C. Aul, Andreas Grüneisen, Wolfgang Kern, Achim Heinecke, W.-D. Ludwig, Wolfgang E. Berdel, C. Fonatsch, Thomas Büchner, Maria Cristina Sauerland, Hubert Serve, Eva Lengfelder, T. Haferlach, and Wolfgang Hiddemann
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Adolescent ,Daunorubicin ,medicine.drug_class ,Antimetabolite ,Tioguanine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Thioguanine ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Mitoxantrone ,business.industry ,Cytarabine ,Myeloid leukemia ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Surgery ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Female ,business ,medicine.drug - Abstract
Purpose: To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML). Materials and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age < 60 years] or 1 g/m2 [age ≥ 60 years] × 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age < 60 years) or 0.5 g/m2 (age ≥ 60 years) × 8 instead of maintenance. Results: A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P = .0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age ≥ 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P = .0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P = .085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P = .026). Conclusion: We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.
- Published
- 2003
45. ACUTE MYELOID LEUKEMIA: TREATMENT OVER 60
- Author
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Jochen Karow, Georg Maschmeyer, Andrea Schumacher, Torsten Haferlach, Eva Lengfelder, Axel Heyll, Herbert Rasche, Maria-Cristina Sauerland, Norbert Frickhofen, Andreas Grüneisen, Claudia Schoch, Wolfgang E. Berdel, Carlo Aul, Wolf-Dieter Ludwig, Leopold Balleisen, Hartmut Eimermacher, Helmut Löffler, Wolfgang Hiddemann, Peter Staib, Bernhard Wörmann, T. Büchner, and Wolf-Dietrich Hirschmann
- Subjects
Oncology ,medicine.medical_specialty ,Allogeneic transplantation ,Daunorubicin ,Antineoplastic Agents ,Disease ,Drug resistance ,Quality of life ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Leukemia ,Treatment Outcome ,Leukemia, Myeloid ,Acute Disease ,Immunology ,biology.protein ,Antibody ,business ,medicine.drug - Abstract
Undertreatment of older patients with acute myeloid leukemia (AML) can explain, in part, their inferior outcome when compared to that of younger patients. In agreement with the benefit seen by patients under age 60 from high-dose cytosine arabinoside (Ara-C), there are dose effects in the over 60s, in particular for daunorubicin, in induction treatment and for the duration of postremission treatment. The use of these effects can partly overcome the mostly unfavorable disease biology in older age AML, as expressed by the absence of favorable and the over-representation of adverse chromosomal abnormalities as well as the expression of drug resistance. We recommend an adequate dosage of 60 mg/m2 daunorubicin on 3 days in combination with standard dose Ara-C and 6-thioguanine given for induction and consolidation, and followed by a prolonged monthly maintenance chemotherapy for at least 1 year's duration. Further improvements in supportive care may help to deliver additional antileukemic cytotoxicity. As a novel approach, nonmyeloablative preparative regimens may open up the possibility of allogeneic transplantation for older patients with AML. Other new options like multidrug resistance modulators, antibody targeted therapies and molecular targeting are under clinical investigation. A questionnaire study in patients with AML showed that, according to patients' self-assessment, intensive and prolonged treatment did not result in a diminished quality of life. This finding did not vary by age, under or over 60 years. As the median age in this disease is more than 60 years, the adequate management of AML in older patients remains the major challenge.
- Published
- 2002
46. Factors influencing life satisfaction in acute myeloid leukemia survivors following allogeneic stem cell transplantation: a cross-sectional study
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Susanne, Amler, Maria Cristina, Sauerland, Christian, Deiters, Thomas, Büchner, and Andrea, Schumacher
- Subjects
Adult ,Male ,Psychiatric Status Rating Scales ,Acute Myeloid Leukemia ,Quality of life ,Depression ,Research ,Hematopoietic Stem Cell Transplantation ,Personal Satisfaction ,Anxiety ,Middle Aged ,Allogeneic stem cell transplantation ,Leukemia, Myeloid, Acute ,Cross-Sectional Studies ,Oncology ,Surveys and Questionnaires ,Adaptation, Psychological ,Humans ,Female ,Life satisfaction ,Survivors ,Aged - Abstract
Background Allogeneic stem cell transplantation (alloSCT) is the preferred option of postremission therapy for high-risk patients suffering from acute myeloid leukemia (AML). Therefore, monitoring life satisfaction (LS) of long-term survivors following alloSCT is becoming increasingly important for oncologists. The aim of the study was to evaluate individual survivor priority of various general and health-related domains of life and their satisfaction with these domains. Furthermore, we investigated the impact of general and health-related LS on resilience, anxiety, depression and quality of life in AML survivors following alloSCT. Methods Forty-one AML survivors (median age at time of assessment = 49.0 years) who had undergone alloSCT (median time since transplantation = 3.1 years) were enrolled in the study. Psychosocial parameters were assessed using the following instruments: FLZM (Questions on Life Satisfaction), EORTC QLQ-C30, HADS (Hospital Anxiety and Depression Scale) and the RS-25 (Resilience Scale-25 items). Correlation analyses were computed to reveal the associations between the different questionnaires. Results Independence from help or care, well-regulated living conditions and financial security contributed positively to LS, whereas being off work due to health-reasons and dissatisfaction with physical aspects were negatively associated to the subjective feelings of overall satisfaction. Moreover, a high quality of life was strongly positively correlated with LS (Spearman’s rho general LS: 0.643 and health-related LS: 0.726, both p
- Published
- 2014
47. Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis
- Author
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Alexander Graf, Max Hubmann, Ulrich Mansmann, Stefan Krebs, Zlatana Pasalic, Bianka Ksienzyk, Annika Dufour, Tobias Herold, Wolfgang E. Berdel, Bernhard J. Woermann, Gerhard Ehninger, Vindi Jurinovic, Martin Bornhäuser, Friedrich Stölzel, Maria Cristina Sauerland, Philipp A. Greif, Sebastian Vosberg, Luise Hartmann, Helmut Blum, C. Röllig, Stefan K. Bohlander, Stephanie Schneider, Klaus H. Metzeler, Purvi M. Kakadia, Karsten Spiekermann, Evelyn Zellmeier, Thomas Büchner, and Wolfgang Hiddemann
- Subjects
Adult ,Male ,Poor prognosis ,Spliceosome ,Adolescent ,Immunology ,Trisomy ,Biology ,Bioinformatics ,Biochemistry ,Disease-Free Survival ,hemic and lymphatic diseases ,Germany ,medicine ,Humans ,neoplasms ,Gene ,Exome sequencing ,Aged ,Aged, 80 and over ,Chromosomes, Human, Pair 13 ,Gene Expression Regulation, Leukemic ,Clinical course ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Neoplasm Proteins ,Up-Regulation ,Survival Rate ,Leukemia, Myeloid, Acute ,Homogeneous ,Cancer research ,Female - Abstract
Isolated trisomy 13 (AML+13) is a rare chromosomal abnormality in acute myeloid leukemia (AML), and its prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and studied their biological characteristics by exome sequencing, targeted sequencing of candidate genes and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, p=0.006; median OS 9.3 vs. 14.8 months, p=0.004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%, of AML+13 patients. Moreover, recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogenous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogenous leukemia subgroup with alterations in a few critical cellular pathways. These studies were registered at clinicaltrials.gov, identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373.
- Published
- 2014
48. Molecular response assessment by quantitativerael-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies patients at high risk for relapse
- Author
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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
- Subjects
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
49. 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
- Subjects
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
50. Remission induction therapy: the more intensive the better?
- Author
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Bernhard Wörmann, Maria-Cristina Sauerland, Detlef Haase, Peter Staib, T. Haferlach, H. E. Reis, Achim Heinecke, T. Büchner, Wolfgang Hiddemann, Wolf-Dietrich Hirschmann, W.-D. Ludwig, Wolfgang E. Berdel, Joachim Hartlapp, Hartmut Eimermacher, Winfried Gassmann, Herbert Rasche, Georg Maschmeyer, Andreas Grüneisen, C. Aul, Jens Uhlig, Helmut Löffler, Leopold Balleisen, Claudia Schoch, Reinhard Andreesen, Hans-Josef Weh, and H. J. Pielken
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Daunorubicin ,medicine.medical_treatment ,Population ,Toxicology ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Remission Induction Therapy ,medicine ,Humans ,Pharmacology (medical) ,Thioguanine ,education ,Aged ,Pharmacology ,Clinical Trials as Topic ,Chemotherapy ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Remission Induction ,Age Factors ,Cytarabine ,Middle Aged ,medicine.disease ,Minimal residual disease ,Regimen ,Leukemia ,Leukemia, Myeloid ,Acute Disease ,Immunology ,business ,medicine.drug - 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 such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to 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 cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.
- Published
- 2001
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