T Büchner

Universitätsklinikum Münster, Muenster, North Rhine-Westphalia, Germany

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Publications (313)1720.25 Total impact

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    ABSTRACT: 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. 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: FLZ(M) (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. 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 < 0.001). A high degree of resilience was also strongly positively correlated with better LS (general LS: 0.700, health-related LS: 0.675, both p < 0.001). Symptoms of anxiety and depression were associated with an impaired general LS (anxiety: -0.674, depression: -0.698, both p < 0.001). Our results indicate that LS should be considered an important key contributor to the survivors' well-being following alloSCT. Thus, identifying protective psychological and physical factors that relieve stressors is of high importance in order to support long-term AML survivors with their special needs.
    Health and Quality of Life Outcomes 12/2015; 13(1):222. DOI:10.1186/s12955-015-0222-8 · 2.10 Impact Factor
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    ABSTRACT: Non-relapse mortality after Allo-SCT has significantly decreased over the last years. Nevertheless, relapse remains a major cause for post SCT mortality in patients with AML and high-risk myelodysplastic syndrome (MDS). In this retrospective single-center analysis, we have analyzed the treatment outcomes of 108 patients with AML or MDS, who relapsed after Allo-SCT. Seventy of these patients (65%) were treated with salvage therapies containing chemotherapy alone, allogeneic cell-based treatment or the combination of both. Thirty-eight patients (35%) received palliative treatment. Median OS after diagnosis of relapse was 130 days. Compared with patients who received chemotherapy alone, response to salvage therapy was significantly improved in patients treated with a combination of chemo- and allogeneic cell-based therapy (CR rate 57% vs 13%, P=0.002). Among risk factors concerning pretreatment characteristics, disease status before first Allo-SCT, and details of transplantation, only the time interval from Allo-SCT to relapse was an independent predictor of response to salvage therapy and OS. These data confirmed that time to relapse after transplantation is an important prognostic factor. Up to now, only patients eligible for treatment regimens containing allogeneic cell-based interventions achieved relevant response rates.Bone Marrow Transplantation advance online publication, 19 January 2015; doi:10.1038/bmt.2014.300.
    Bone Marrow Transplantation 01/2015; DOI:10.1038/bmt.2014.300 · 3.47 Impact Factor
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    ABSTRACT: Abstract Wilms' Tumor 1 (WT1) is known to be highly expressed in acute promyelocytic leukemia (APL) but information on its impact on prognosis is lacking. WT1 expression was analyzed in bone marrow samples of 79 APL patients at initial diagnosis. Patients had a differing outcome according to their level of WT1 expression. In patients who achieved a CR, low or high WT1 expression was significantly associated with inferior overall survival (OS) compared to intermediate WT1 expression (49% high vs. 63% for low vs. 93% for intermediate expressers; p=0.008). Moreover, there were significant differences in relapse free survival (RFS) between the three expression groups (42% for WT1(high), 63% for WT1(low) and 83% for WT1(int); p=0.047). In multivariable analysis WT1 expression showed independent prognostic impact on OS of responders to induction therapy. In conclusion, the level of WT1 expression can add prognostic information in APL risk stratification.
    Leukemia and Lymphoma 11/2014; DOI:10.3109/10428194.2014.990011 · 2.61 Impact Factor
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    ABSTRACT: NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML.
    PLoS ONE 10/2014; 9(10):e109759. DOI:10.1371/journal.pone.0109759 · 3.53 Impact Factor
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    ABSTRACT: Background The aim of this study was to analyze the long-term survival of AML patients with CEBPA mutations.Patients and methodsWe investigated 88 AML patients with a median age of 61 years and (1) cytogenetically normal AML (CN-AML), (2) monoallelic (moCEBPA) or biallelic (biCEBPA) CEBPA mutation, and (3) intensive induction treatment. 60/88 patients have been described previously with a shorter follow-up.ResultsMedian follow-up time was 9.8 years (95% CI: 9.4-10.1 years) compared to 3.2 and 5.2 years in our former analyses. Patients with biCEBPA survived significantly longer compared to those with moCEBPA (median overall survival (OS) 9.6 years vs. 1.7 years, p¿=¿0.008). Patients¿¿¿60 years and biCEBPA mutations showed a favorable prognosis with a 10-year OS rate of 81%.Both, bi- and moCEBPA-mutated groups had a low early death (d60) rate of 7% and 9%, respectively. Complete remission (CR) rates for biCEBPA- and moCEBPA-mutated patients were 82% vs. 70% (p¿=¿0.17). biCEBPA-mutated patients showed a longer relapse free survival (RFS) (median RFS 9.4 years vs. 1.5 years, p¿=¿0.021) and a lower cumulative incidence of relapse (CIR) compared to moCEBPA-mutated patients. These differences in OS and RFS were confirmed after adjustment for known clinical and molecular prognostic factors.Conclusions In this long-term observation we confirmed the favorable prognostic outcome of patients with biCEBPA mutations compared to moCEBPA-mutated CN-AML. The high probability of OS (81%) in younger patients is helpful to guide intensity of postremission therapy.
    Journal of Hematology & Oncology 09/2014; 7(1):55. DOI:10.1186/s13045-014-0055-7 · 4.93 Impact Factor
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    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.
    Blood 06/2014; 124(8). DOI:10.1182/blood-2013-12-540716 · 9.78 Impact Factor
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    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 is lacking. Therefore, the value of flow MRD detection was determined during aplasia in 178 patients achieving complete remission after treatment according to AMLCG induction protocols. Flow MRD-positivity during aplasia predicted poor outcome (5-year relapse-free survival (RFS) 16% vs 43%, P<0.001) 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 not impacted by morphological blast count during aplasia nor by MRD status post-induction. 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 post-remission therapy for patients at high risk of relapse.Leukemia accepted article preview online, 10 June 2014; doi:10.1038/leu.2014.186.
    Leukemia 06/2014; 29(2). DOI:10.1038/leu.2014.186 · 9.38 Impact Factor
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    ABSTRACT: Monitoring of minimal residual disease represents an important diagnostic tool to identify patients with acute myeloid leukemia at high risk for relapse. In this study the prognostic potential of minimal residual disease monitoring by quantitative real-time PCR of NPM1 mutations of patients treated in the AMLCG trials 1999, 2004 and 2008 was investigated. Minimal residual disease monitoring was performed in 588 samples of 158 NPM1 mutation A, B and D positive patients at diagnosis, in aplasia, after induction therapy, after consolidation therapy, and during follow-up with a sensitivity of 10-6. 127 patients (80.4%) achieved complete remission after induction therapy and of these 56 patients (44.1%) relapsed. At each checkpoints, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 revealed 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 cut-off positive patients versus 26.4% for cut-off negative patients, respectively. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separates 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 individual minimal residual disease course is an important prognostic factor and could be included into clinical trials for the guidance of postremission therapy. Trials were registered at www.clinicaltrials.gov (#NCT01382147, #NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230).
    Haematologica 05/2014; DOI:10.3324/haematol.2014.104133 · 5.87 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Journal of Clinical Oncology 04/2014; 32(15). DOI:10.1200/JCO.2013.52.3480 · 17.88 Impact Factor
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    ABSTRACT: About 30% of patients with acute myeloid leukemia (AML) harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD) and point mutations of the second tyrosine kinase domain (TKD). It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations - including two novel mutations - showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.
    PLoS ONE 03/2014; 9(3):e89560. DOI:10.1371/journal.pone.0089560 · 3.53 Impact Factor
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    ABSTRACT: The majority of patients with acute myeloid leukemia (AML) who achieve complete remission (CR) relapse with conventional postremission chemotherapy. Allogeneic stem-cell transplantation (alloSCT) might improve survival at the expense of increased toxicity. It remains unknown for which patients alloSCT is preferable. We compared the outcome of 185 matched pairs of a large multicenter clinical trial (AMLCG99). Patients younger than 60 years who underwent alloSCT in first remission (CR1) were matched to patients who received conventional postremission therapy. The main matching criteria were AML type, cytogenetic risk group, patient age, and time in first CR. In the overall pairwise compared AML population, the projected 7-year overall survival (OS) rate was 58% for the alloSCT and 46% for the conventional postremission treatment group (P = .037; log-rank test). Relapse-free survival (RFS) was 52% in the alloSCT group compared with 33% in the control group (P < .001). OS was significantly better for alloSCT in patient subgroups with nonfavorable chromosomal aberrations, patients older than 45 years, and patients with secondary AML or high-risk myelodysplastic syndrome. For the entire patient cohort, postremission therapy was an independent factor for OS (hazard ratio, 0.66; 95% CI, 0.49 to 0.89 for alloSCT v conventional chemotherapy), among age, cytogenetics, and bone marrow blasts after the first induction cycle. AlloSCT is the most potent postremission therapy for AML and is particularly active for patients 45 to 59 years of age and/or those with high-risk cytogenetics.
    Journal of Clinical Oncology 12/2013; 32(4). DOI:10.1200/JCO.2013.50.5768 · 17.88 Impact Factor
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    ABSTRACT: Chemo-modulation of cytarabine by fludarabine has been attributed with a higher anti-leukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, 281 evaluable) were randomly assigned to SHAI (cytarabine 1 g/m(2) bid days 1-2 and 8-9 [3 g/m(2) for patients60 years with refractory AML or2nd relapse], idarubicin 10 mg/m(2) daily days 3-4 and 10-11) or F-SHAI (SHAI with fludarabine 15 mg/m(2) 4 hours prior to cytarabine). While complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time-to-treatment failure from 2.04 months to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic SCT, with a significantly higher number of patients in CR or CRi in the F-SHAI group (22% versus 10%, P<0.01). In conclusion, fludarabine has a beneficial though moderate impact on the antileukemic efficacy of high-dose cytarabine based salvage therapy for relapsed and refractory AML.Leukemia accepted article preview online, 22 October 2013; doi:10.1038/leu.2013.297.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2013; DOI:10.1038/leu.2013.297 · 9.38 Impact Factor
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    ABSTRACT: We investigated whether octogenarian patients with acute myeloid leukemia enrolled onto Cooperative Group clinical trials and treated with intensive induction therapy could be cured, and whether karyotype and selected molecular markers had any prognostic significance in these patients. Among 138 patients with cytogenetic results, normal karyotype was the most common (47.1%) followed by complex karyotype (14.5%) and sole +8 (9.4%). Among these patients, the relapse-free survival (RFS) rate at 1 year was 37% and 13% at 3 years, and the respective overall survival (OS) rates were 24% and 8%. Whereas the 90 patients who survived beyond 30 days had the same RFS rates, their 1-year and 3-year OS rates were 36% and 11%, respectively. Of the 66 patients surviving beyond 30 days who could be classified into the European LeukemiaNet (ELN) Genetic Groups, those in the Intermediate-I Group had better OS than patients in the Adverse Group (P=.01). Among patients with cytogenetically normal acute myeloid leukemia who were tested for the ELN-associated molecular alterations, FLT3-internal tandem duplication and NPM1 mutations, FLT3-internal tandem duplication (detected in 29% of patients) did not associate with OS (P=.31), whereas NPM1 mutations (30%) were associated with a significantly longer OS (P=.002). We conclude that intensive induction is effective and indicated in selected octogenarians with acute myeloid leukemia, that their OS varies among the ELN Genetic Groups and that NPM1 mutations may be of prognostic significance among octogenarian patients with cytogenetically normal acute myeloid leukemia.
    Haematologica 10/2013; 99(2). DOI:10.3324/haematol.2013.092072 · 5.87 Impact Factor
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    ABSTRACT: The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors, RUNX1 and CBFB, respectively, are found in 15-20% of adult de novo AML cases and are associated with a favourable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the ATP-binding domain (TKD1) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5/84, 6%; 1/36, 3%). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD, confers resistance to the FLT3 PTK inhibitors PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend towards a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in CBF leukemias and suggests a defined subgroup of CBF leukemias. Registered at www.clinicaltrials.gov: AMLCG-1999 trial (NCT00266136).
    Blood 07/2013; 122(10). DOI:10.1182/blood-2013-01-476473 · 9.78 Impact Factor
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    ABSTRACT: After allo-SCT, analysis of CD34(+) lineage-specific donor cell chimerism (DCC) is a sensitive method for monitoring minimal residual disease in patients with AML or myelodysplastic syndrome (MDS) with CD34 expression. To substantiate evidence of whether immune interventions in patients with impending relapse, defined by incomplete lineage-specific DCC, may prevent hematological relapse, we performed a retrospective nested case control study. Unsorted and lineage-specific DCC were measured in 134 patients. Forty-three patients had an incomplete CD34(+)-DCC with no other evidence of relapse. After immediate tapering of immunosuppressive treatment (30 patients) and/or infusion of donor lymphocytes (10 patients), 21 patients remained in remission (conversion to complete lineage-specific DCC) and 22 relapsed. Relapse-free survival at 3 years of the 91 patients with stable DCC and of the 43 patients with incomplete DCC was 74% (95% confidence interval (CI), 64-83%) and 40% (95% CI, 24-58%), respectively. OS rates were 79% (95% CI, 70-88%) and 52% (95% CI, 35-69%), respectively. These results, with 49% of patients with impending relapse successfully treated with immune intervention, highly suggest that analysis of CD34(+)-DCC is an important tool for monitoring and the management of AML and MDS patients after allo-SCT.Bone Marrow Transplantation advance online publication, 4 February 2013; doi:10.1038/bmt.2013.2.
    Bone marrow transplantation 02/2013; 48(8). DOI:10.1038/bmt.2013.2 · 3.47 Impact Factor
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    ABSTRACT: PURPOSETo 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.ResultsA 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.
    Journal of Clinical Oncology 02/2013; DOI:10.1200/JCO.2012.44.3184 · 17.88 Impact Factor
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    ABSTRACT: We evaluated the prognostic value of BAALC expression in 86 patients with acute promyelocytic leukemia (APL). At 10 years, the overall survival (OS) was 66% in all patients and 75% in patients who achieved a complete remission (CR). Patients in the BAALC(low) group showed an OS of 87% as compared to 60% in the BAALC(high) group (p=0.019). This difference was more pronounced in treatment responders (92% vs. 70%; p=0.035). In multivariate analyses low BAALC expression retained its prognostic relevance. In conclusion, BAALC expression analysis might be useful in further risk stratification in APL patients.
    Leukemia research 12/2012; 37(4). DOI:10.1016/j.leukres.2012.11.018 · 2.69 Impact Factor
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    ABSTRACT: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm. This trial is registered at clinical trials.gov (identifier: NCT00915252).
    PLoS ONE 12/2012; 7(12):e52695. DOI:10.1371/journal.pone.0052695 · 3.53 Impact Factor
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    ABSTRACT: In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens.
    Annals of Hematology 12/2012; 92(4). DOI:10.1007/s00277-012-1648-2 · 2.40 Impact Factor
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    ABSTRACT: The origin of aberrant DNA methylation in cancer remains largely unknown. In this study, we elucidated the DNA methylome in primary Acute Promyelocytic Leukemia (APL) and the role of PML-RARα in establishing these patterns. APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34+ cells, promyelocytes and remission bone marrow. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score and Flt3-mutation status characterized methylation subtypes. Transcription factor binding sites, e.g. c-myc binding sites were associated with low methylation. SUZ12 and REST binding sites identified in embryonic stem cells were, however, preferentially DNA hypermethylated in APL. Unexpectedly, PML-RARα binding sites were also protected from aberrant DNA methylation in APL. In line, myeloid cells from pre-leukemic PML-RARα knock-in mice did not show altered DNA methylation and expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. ATRA treatment of APL blasts did also not result in immediate DNA methylation changes. These results suggest that aberrant DNA methylation is associated with leukemia phenotype but not required for PML-RARα-mediated initiation of leukemogenesis.
    Blood 11/2012; DOI:10.1182/blood-2012-08-448860 · 9.78 Impact Factor

Publication Stats

9k Citations
1,720.25 Total Impact Points

Institutions

  • 1990–2015
    • Universitätsklinikum Münster
      • • Medizinische Klinik und Poliklinik A
      • • Medizinische Klinik B
      • • Institut für Humangenetik
      Muenster, North Rhine-Westphalia, Germany
    • EUREGIO-KLINIK Albert-Schweitzer-Straße GmbH
      Nordhorn, Lower Saxony, Germany
  • 1974–2015
    • University of Münster
      • • Department of Medicine, Hematology and Oncology
      • • Department of Internal Medicine
      Muenster, North Rhine-Westphalia, Germany
  • 1999–2012
    • Ludwig-Maximilian-University of Munich
      • Department of Internal Medicine II
      München, Bavaria, Germany
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2010
    • Münchner Leukämie Labor GmbH
      München, Bavaria, Germany
  • 2007
    • Boehringer Ingelheim
      Ingelheim-Mitte, Rheinland-Pfalz, Germany
  • 2001–2007
    • University of Hamburg
      Hamburg, Hamburg, Germany
  • 2005–2006
    • University of Cologne
      Köln, North Rhine-Westphalia, Germany
  • 2000–2006
    • Universität Heidelberg
      • • Medical University Clinic and Polyclinic
      • • II. Medical Clinic
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2004
    • Universität Ulm
      • Department of Internal Medicine
      Ulm, Baden-Wuerttemberg, Germany
  • 2002
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1994–1998
    • Georg-August-Universität Göttingen
      • Faculty of Medicine
      Göttingen, Lower Saxony, Germany
  • 1997
    • Haematology Oncology Practice Altona
      Hamburg, Hamburg, Germany
  • 1990–1993
    • Freie Universität Berlin
      • Department of Hematology
      Berlin, Land Berlin, Germany
  • 1991
    • Medical College of Wisconsin
      Milwaukee, Wisconsin, United States
  • 1986–1987
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany