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Susanne Schnittger

Publications and source records attributed to Susanne Schnittger.

At least 37 records · Page 2Linked to original sources
PubMed2005

Treatment of older patients with AML.

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 60 mg/(m2day) 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.

Adult↗
PubMed2005

Modern diagnostics in acute leukemias.

Acute leukemias are a heterogeneous group of diseases. The different subtypes are characterized by certain clinical features and specific laboratory findings. Large clinical trials have confirmed the important impact of the underlying biology of each subtype for clinical outcome. Improvements in patient's treatment resulting in better survival rates are closely linked to the biological understanding of the disease subtypes, which is assessed by specific diagnostic approaches. Thus, several diagnostic techniques are mandatory at diagnosis for classification and for individual therapeutic decisions. Furthermore they are also needed for follow up studies focusing especially on minimal residual disease (MRD) to guide further treatment decisions based on the response of the disease to given treatment protocols. Only by using a comprehensive diagnostic panel including cytomorphology, cytochemistry, multiparameter flow cytometry (MFC), cytogenetics, fluorescence in situ hybridization (FISH) and molecular genetic methods the correct diagnosis in acute leukemias can be established today. The results serve as a mandatory prerequisite for individual treatment strategies and for the evaluation of treatment response using especially newly defined and highly specific MRD markers.

Biomarkers, Tumor↗
PubMed2005

Monitoring of minimal residual disease in acute myeloid leukemia.

Monitoring minimal residual disease (MRD) becomes increasingly important in the risk-adapted management of patients with acute myeloid leukemia (AML). The two most sensitive and quantitative methods for MRD detection are multiparameter flow cytometry (MFC) and real-time polymerase chain reaction (QRT-PCR). Fusion gene-specific PCR in AML is based on the RNA level, and thus in contrast to MFC expression levels rather than cell counts are assessed. For both methods independent prognostic values have been shown. The strong power of MFC has been shown mainly in the assessment of early clearance of the malignant clone. MRD levels in AML with fusion genes have the strongest prognostic power after the end of consolidation therapy. In addition, with QRT-PCR highly predictive initial expression levels can be assessed. With both methods early detection of relapse is possible. So far, validated PCR-based MRD was done with fusion genes that are detectable in only 20-25% of all AML MFC is superior since it is applicable for most AML. However, QRT-PCR is still more sensitive in most cases. Thus, it is desirable to establish new molecular markers for PCR-based studies. Large clinical trials will determine the role and place of immunologic and PCR-based monitoring in the prognostic stratification of patients with AML.

Biomarkers, Tumor↗
PubMed2005

Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype.

Nucleophosmin (NPM1) exon-12 gene mutations are the hallmark of a large acute myelogenous leukemia (AML) subgroup with normal karyotype, but their prognostic value in this AML subset has not yet been determined. We screened 401 AML patients with normal karyotype treated within the German AML Cooperative Group Protocol 99 (AMLCG99) study for NPM1 mutations. Results were related with partial tandem duplications within the MLL gene (MLL-PTD), Fms-like tyrosine kinase 3-length mutations (FLT3-LM), the tyrosine kinase domain of FLT3 (FLT3-TKD), NRAS, KIT, and CEBPA mutations and with clinical characteristics and outcome. NPM1 mutations were detected in 212 (52.9%) of 401 patients. Fourteen mutations, including 8 new variants, were identified. NPM1-mutated cases associated frequently with FLT3 mutations but rarely with other mutations. The NPM1-mutated group had a higher complete remission (CR) rate (70.5% vs 54.7%, P = .003), a trend to a longer overall survival (OS; median 1012 vs 549 days, P = .076), and significantly longer event-free survival (EFS; median 428 vs 336 days; P = .012). The favorable impact of NPM1 mutations on OS and EFS clearly emerged in the large group (264 [66.8%] of 395 cases) of normal-karyotype AML without FLT3-LM. This positive effect was lost in the presence of a concomitant FLT3-LM, since survival of the NPM1+/FLT3-LM+ double positive was similar to NPM1-/FLT3-LM+ cases. In conclusion, this study demonstrates that NPM1+/FLT3-LM- mutations are an independent predictor for a favorable outcome in AML with normal karyotype.

Adolescent↗
PubMed2005

The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice.

The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO-positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO-positive leukemias.

Animals↗
PubMed2005

Role of gene expression profiling for diagnosing acute leukemias.

Cytomorphology and cytochemistry in combination with multiparameter immunophenotyping today are the standard methods for establishing the diagnosis of acute leukemias. In addition, cytogenetics, fluorescence in situ hybridization, and polymerase chain reaction based assays provide important information regarding biologically defined and prognostically relevant subgroups and allow a comprehensive diagnosis of well defined subentities. With regard to the clinical setting a better understanding of the clinical course of distinct biologically defined disease subtypes is needed to select disease-specific therapeutic approaches. Paralleling the increase in knowledge on deregulated pathways in leukemia the development of new therapeutics is accelerated and therefore requires a detailed and comprehensive diagnostic tool. Revealing and quantifying the expression status of many ten thousands of genes in a single analysis the microarray technology holds this potential to become an essential tool for the molecular classification of leukemias. It may therefore be used as a routine method for diagnostic purposes in the near future. Furthermore, it is anticipated that new biologically defined and clinically relevant subtypes of leukemia will be identified based on gene expression profiling. This method may therefore guide therapeutic decisions.

Acute Disease↗
PubMed2005

Global approach to the diagnosis of leukemia using gene expression profiling.

Accurate diagnosis and classification of leukemias are the bases for the appropriate management of patients. The diagnostic accuracy and efficiency of present methods may be improved by the use of microarrays for gene expression profiling. We analyzed gene expression profiles in 937 bone marrow and peripheral blood samples from 892 patients with all clinically relevant leukemia subtypes and from 45 nonleukemic controls by U133A and U133B GeneChip arrays. For each subgroup, differentially expressed genes were calculated. Class prediction was performed using support vector machines. Prediction accuracy was estimated by 10-fold cross-validation and was assessed for robustness in a 100-fold resampling approach using randomly chosen test sets consisting of one third of the samples. Applying the top 100 genes of each subgroup, an overall prediction accuracy of 95.1% was achieved that was confirmed by resampling (median, 93.8%; 95% confidence interval, 91.4%-95.8%). In particular, acute myeloid leukemia (AML) with t(15;17), AML with t(8;21), AML with inv(16), chronic lymphatic leukemia (CLL), and pro-B-cell acute lymphoblastic leukemia (pro-B-ALL) with t(11q23) were classified with 100% sensitivity and 100% specificity. Accordingly, cluster analysis completely separated all 13 subgroups analyzed. Gene expression profiling can predict all clinically relevant subentities of leukemia with high accuracy.

Adolescent↗
PubMed2005

Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype.

In acute myeloid leukemia (AML), constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplications (FLT3-ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (FLT3-TKD), as well as point mutations of the NRAS gene (NRAS-PM) are among the most frequent somatic gene mutations. To elucidate whether these mutations cause aberrant signal transduction in AML, we used gene expression profiling in a series of 110 newly diagnosed AML patients with normal karyotype. The different algorithms used for data analysis revealed highly concordant sets of genes, indicating that the identified gene signatures are specific for each analysed subgroup. Whereas samples with FLT3-ITD and FLT3-TKD could be separated with up to 100% accuracy, this did not apply for NRAS-PM and wild-type samples, suggesting that only FLT3-ITD and FLT3-TKD are associated with an apparent signature in AML. The set of discriminating genes included several known genes, which are involved in cell cycle control (CDC14A, WEE1), gene transcription (HOXB5, FOXA1), and signal transduction (SMG1). In conclusion, we showed that unique gene expression patterns can be correlated with FLT3-ITD and FLT3-TKD. This might lead to the identification of further pathogenetic relevant candidate genes particularly in AML with normal karyotype.

Gene Expression Regulation, Neoplastic↗
PubMed2005

Conventional cytogenetics of myeloproliferative diseases other than CML contribute valid information.

In chronic myeloproliferative disorders other than CML (CMPD) recurrent cytogenetic abnormalities occur, but specific patterns of chromosomal aberrations in the specific entities have so far not been detected. Thus, the value of conventional cytogenetics in the routine diagnostic setting of CMPD remains to be clarified. We performed a cytogenetic study on 409 patients with different CMPD [polycythemia vera, essential thrombocytosis (ET), idiopathic osteomyelofibrosis, chronic myelomonocytic leukemia (proliferative subtype), idiopathic hypereosinophilic syndrome (HES), myeloproliferative syndrome (unclassifiable)] and on 102 patients with suspected CMPD. Cytogenetic abnormalities occurred in different frequencies ranging from 3 to 40% depending on the subtype, and showed some specific differences with respect to their type. The highest frequency and the most complex pattern of clonal aberrations were observed in idiopathic osteomyelofibrosis. However, clonal aberrations were also found in 10% of patients with suspected CMPD establishing the diagnosis of a malignant disease. In conclusion, cytogenetics are essential in the routine diagnostic setting of CMPD or cases suspicious for CMPD. In ET and in HES the aberration rate was only 3 and 7%, respectively. Thus, cytogenetics can be omitted. However, in some of these cases molecular procedures should be integrated into the routine diagnostic process.

Adult↗
PubMed2005

Pattern robustness of diagnostic gene expression signatures in leukemia.

Microarray technology has been proposed as an addition to the methods in current use for diagnosing leukemia. Before a new technology can be used in a diagnostic setting, the method has to be shown to produce robust results. It is known that, given the technical aspects of specimen sampling and target preparation, global gene expression patterns can change dramatically. Various parameters such as RNA degradation, shipment time, sample purity, and patient age can principally influence measured gene expression. However, thus far, no information has been available on the robustness of a diagnostic gene expression signature. We demonstrate here that for a subset of acute leukemia, expression profiling is applicable in a diagnostic setting, considering various influencing parameters. With the use of a set of differentially expressed genes, that is, a diagnostic gene expression signature, four genetically defined acute myeloid leukemia subtypes with recurrent chromosomal aberrations can clearly be identified. In addition, we show that preparation by different operators and using different sample-handling procedures did not impair the robustness of diagnostic expression signatures. In conclusion, our results provide additional support for the applicability of microarrays in a diagnostic setting, and we have been encouraged to enroll patients in a prospective study in which microarrays will be tested as an additional routine diagnostic method in parallel with standard diagnostic procedures.

Adult↗
PubMed2005

AML M3 and AML M3 variant each have a distinct gene expression signature but also share patterns different from other genetically defined AML subtypes.

Acute promyelocytic leukemia (APL) with t(15;17) appears in two phenotypes: AML M3, with abnormal promyelocytes showing heavy granulation and bundles of Auer rods, and AML M3 variant (M3v), with non- or hypogranular cytoplasm and a bilobed nucleus. We investigated the global gene expression profiles of 35 APL patients (19 AML M3, 16 AML M3v) by using high-density DNA-oligonucleotide microarrays. First, an unsupervised approach clearly separated APL samples from other AMLs characterized genetically as t(8;21) (n = 35), inv(16) (n = 35), or t(11q23)/MLL (n = 35) or as having a normal karyotype (n = 50). Second, we found genes with functional relevance for blood coagulation that were differentially expressed between APL and other AMLs. Furthermore, a supervised pairwise comparison between M3 and M3v revealed differential expression of genes that encode for biological functions and pathways such as granulation and maturation of hematologic cells, explaining morphologic and clinical differences. Discrimination between M3 and M3v based on gene signatures showed a median classification accuracy of 90% by use of 10-fold CV and support vector machines. Additional molecular mutations such as FLT3-LM, which were significantly more frequent in M3v than in M3 (P < 0.0001), may partly contribute to the different phenotypes. However, linear regression analysis demonstrated that genes differentially expressed between M3 and M3v did not correlate with FLT3-LM.

Adolescent↗
PubMed2005

Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized by genomic imbalances and a specific gene expression profile.

Acute myeloid leukemia (AML) with a complex aberrant karyotype is a distinct biological entity. It is characterized by: (1) a sharp increase in incidence above age 50; (2) a characteristic pattern of chromosomal gain and, especially, loss, that is, of 5q14q33, 7q32q35, and 17p13, translating into reduced expression of genes in these regions; (3) a unique gene expression pattern including up-regulation of genes involved in DNA repair; (4) a high incidence of TP53 deletions and/or mutations; and (5) an overall unfavorable prognosis. Further unraveling the biology of AML with a complex aberrant karyotype by gene expression profiling may provide deeper insights into the pathogenesis of as well as the reasons for chemoresistance in this AML subtype. These data may be the basis for developing targeted therapeutic strategies to increase the cure rate in patients with AML and a complex aberrant karyotype.

Acute Disease↗
PubMed2005

Additional clonal abnormalities in Philadelphia-positive ALL and CML demonstrate a different cytogenetic pattern at diagnosis and follow different pathways at progression.

The cytogenetic patterns in addition to the Philadelphia translocation in Philadelphia-positive (Ph+) ALL and chronic myeloid leukemia (CML) is heterogenous. We investigated 154 patients with Ph+ ALL at diagnosis or at relapse and 174 patients with different phases of CML. Ph+ ALL at diagnosis demonstrated a heterogenous pattern with a high frequency of numerical and structural chromosomal aberrations. CML at diagnosis presented with rare additional chromosomal changes. In Ph+ ALL, the pathway from diagnosis to relapse was characterized by the acquisition of a higher number of chromosomal aberrations, but the pattern of frequent aberrations at relapse did not differ from that observed at diagnosis. In contrast, in CML the pathway from chronic to the advanced phases was characterized by the acquisition of new chromosomal changes and by the development of karyotype complexity. In addition, the investigation of 10 cases of lymphoid blast crisis of CML showed significant differences in the karyotype in comparison to Ph+ ALL at diagnosis. Therefore, the karyotype can be helpful in discriminate de novo lymphoid blast crisis of CML from de novo Ph+ ALL. In conclusion, we were able to demonstrate that the cytogenetic patterns of Ph+ ALL and of CML are different at diagnosis and furthermore follow different pathways during progression or relapse.

Blast Crisis↗
PubMed2005

Blast count and cytogenetics correlate and are useful parameters for the evaluation of different phases in chronic myeloid leukemia.

Staging of chronic myeloid leukemia (CML) phases is based on cytomorphological criteria that vary considerably between different staging systems. Thus, staging of CML is heterogeneous and causes problems with respect to the comparison of therapeutical strategies and clinical outcome. We evaluated 59 patients with CML in different stages of the disease. In order to define which cytomorphological parameters correlate with cytogenetics we investigated cytomorphology and cytogenetics in parallel in all cases. As a result, bone marrow blast count demonstrated a highly significant correlation with the respective cytogenetic results of the patients and was clearly linked to the frequency and complexity of clonal evolution. We therefore propose to focus staging systems of CML on the correlation of the percentage of bone marrow blasts and the cytogenetic results.

Blast Crisis↗
PubMed2005

Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia.

In the present study 170 newly diagnosed acute promyelocytic leukaemia patients (M3: n = 121; M3v: n = 49) were molecularly characterised with respect to PML breakpoint and additional molecular mutations. In total, 83 patients were positive for bcr1 (49%), five for bcr2 (3%) and 82 for bcr3 (48%). Bcr3 was more frequent in M3v (65.3%) compared with M3 (41.3%) (P = 0.005). Cases with bcr3 showed a significantly higher white blood cell count (median: 3.65 x 10(9)/l vs. 1.59 x 10(9)/l, P = 0.003), as well as a higher PML-RARAABL expression ratio (14.8% vs. 72.7%, P < 0.005) compared with bcr1. FLT3-length-mutations were detected more frequently together with bcr3 compared with bcr1 (56.5% vs. 19.4%, P < 0.001) and in M3v compared with M3 (64.5% vs. 24.1%, P < 0.005). FLT3 tyrosine kinase mutations were found in eight cases (6.4%) and were distributed equally within the total group. Analysis for further mutations revealed no MLL-PTD and KIT mutations and only two cases of 99 analysed (2%) with NRAS mutations. FLT3-mutations were detected in 62 of 139 cases (44.6%) and associated with a significant lower overall survival (P = 0.0339). In addition, cases with bcr3 showed a tendency for a worse event-free survival (P = 0.0795) compared with the bcr1 group.

Adolescent↗
PubMed2005

Detection of t(14;18)(q32;q21) in B-cell chronic lymphocytic leukemia.

Cytomorphologic testing and multiparameter flow cytometry are the mainstays in diagnosing B-cell chronic lymphocytic leukemia, whereas fluorescence in situ hybridization that targets the translocation t(14;18)(q32;q21) often is used to identify follicular lymphoma. Therapy is highly diverse between both diseases. We describe a case with cytomorphologically and immunologically proven B-cell chronic lymphocytic leukemia in which t(14;18)(q32;q21) was found.

Chromosomes, Human, Pair 14↗