Publications (84)548.18 Total impact
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Article: Molecular cytogenetic monitoring from CD34+ peripheral blood cells in myelodysplastic syndromes: First results from a prospective multicenter German diagnostic study.
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ABSTRACT: The gold standard of cytogenetic analysis in myelodysplastic syndromes (MDS) is conventional chromosome banding (CCB) analysis of bone marrow (BM) metaphases. Most aberrations can also be detected by fluorescence-in situ-hybridization (FISH). For this prospective multicenter German diagnostic study (www.clinicaltrials.gov: #NCT01355913) 360 patients, as yet, were followed up to 3 years by sequential FISH analyses of immunomagnetically enriched CD34+ peripheral blood (PB) cells using comprehensive FISH probe panels, resulting in a total number of 19,516 FISH analyses. We demonstrate that CD34+ PB FISH correlates significantly with CCB analysis and represents a feasible method for a reliable non-invasive cytogenetic monitoring from PB.Leukemia research 04/2013; · 2.36 Impact Factor -
Article: Prognostic significance of expression levels of stem cell regulators MSI2 and NUMB in acute myeloid leukemia.
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ABSTRACT: Deregulation of the hematopoietic stem cell (HSC) compartment represents a hallmark of acute myeloid leukemia (AML). Recently, in vivo screening for genes that are involved in the regulation of HSCs has led to the discovery of Musashi-2 (MSI2) as a key regulator of HSCs and as a suppressor of NUMB. In order to analyze the prognostic importance of MSI2 and NUMB expression in AML, MSI2 and NUMB transcript levels from 454 AML patients treated in multicenter trials AML SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295, and 38 healthy volunteers were analyzed by reverse transcriptase PCR in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, DNMT3A, NRAS, WT1, KIT, MN1, BAALC, ERG, and WT1). In AML, patients with high MSI2 expression were more likely to be FLT3-ITD positive (P < .001), NPM1 (P < .001), and DNMT3A (P = .003) mutated. Overall survival (OS) was shorter in AML patients with high MSI2 expression (hazard ratio, 1.48; 95 % confidence interval, 1.13-1.95, P = .005). However, relapse-free survival (RFS, P = .15) and complete remission (CR, P = .39) rates were not influenced by MSI2 expression. In multivariate analysis, MSI2 expression remained an independent prognostic factor for OS (P = .03). NUMB expression had no impact on survival (OS, P = .47; RFS, P = .59) and CR rate (P = .39). MSI2 but not NUMB is associated with shorter OS in AML patients and may indicate a more aggressive form of AML.Annals of Hematology 12/2012; · 2.62 Impact Factor -
Article: Decitabine induces very early in vivo DNA methylation changes in blasts from patients with acute myeloid leukemia.
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ABSTRACT: In vivo effects of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (DAC) upon the epigenome of acute myeloid leukemia (AML) patients are scarcely studied in primary blasts. Here, we sequentially assessed DNA methylation and transcriptome changes in myeloblasts of DAC-treated AML patients. DNA methylation changes were detected in all patients already after the first series of infusion (median: 6 days). LINE1 analysis indicated global DNA methylation decrease in 7/8 patients. Gene-specific hypomethylating effects were not directly linked to mRNA expression changes. In conclusion, complex DAC-induced DNA methylation changes occur very early and imply mechanisms distinct from non-hypomethylating cytosine analogs.Leukemia research 11/2012; · 2.36 Impact Factor -
Article: When Azanucleoside Treatment Can Be Curative: Nonintensive Bridging Strategy Before Allografting in Older Patients With Myelodysplastic Syndrome/Acute Myeloid Leukemia.
Journal of Clinical Oncology 11/2012; · 18.37 Impact Factor -
Article: Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG).
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ABSTRACT: In this study we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. One hundred and seventy-six patients, all enrolled on prospective treatment trials, were studied for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least one gene mutation with RAS being affected in 53% [45% NRAS; 13% KRAS] of the cases, followed by KIT (37%), and FLT3 [17%; FLT3-TKD (14%), FLT3-ITD (5%)]. None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation [hazard ratio (HR)=1.67; P=.04], log(10)(WBC) (HR=1.33; P=.02), and trisomy 22 (HR=0.54; P=.08) were relevant factors for relapse-free survival; for overall survival FLT3 mutation (HR=2.56; P=.006), trisomy 22 (HR=0.45; P=.07), trisomy 8 (HR=2.26; P=.02), age (difference of 10 years, HR=1.46; P=.01), and therapy-related AML (HR 2.13; P=.14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and TKD mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t(16;16).Blood 10/2012; · 9.90 Impact Factor -
Article: MeDIP coupled with a promoter tiling array as a platform to investigate global DNA methylation patterns in AML cells.
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ABSTRACT: Hypermethylation of CpGs in promoter regions and subsequent changes in gene expression are common features in acute myeloid leukemia (AML). Genome-wide studies of the methylome are not only useful to understand changes in DNA methylation and gene regulation but also to identify potential targets for antileukemic treatment. Here we performed methylated DNA immunoprecipitation (MeDIP) in the AML cell line HL-60 and donor-derived CD34+ cells, followed by hybridization on a human promoter tiling array. The comparative analysis of HL-60 versus CD34+ cells revealed differentially methylated promoter regions including genes that are frequently methylated in AML, such as p15/INK4B, OLIG2, RARß2 and estrogen receptor. Microarray data was validated by quantitative pyrosequencing. We corroborate previous reports that MeDIP, in our study combined with a promoter tiling array (MeDIP-Chip), is a robust method to identify genes that are differentially methylated in AML cells in a genome-wide manner, and is thus useful to identify new epigenetic targets for therapeutic or prognostic research.Leukemia research 10/2012; · 2.36 Impact Factor -
Article: Clinical results with the DNA hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in patients with myelodysplastic syndromes: an update.
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ABSTRACT: Patients with myelodysplastic syndromes (MDS), especially those with high-risk disease, other comorbidities, or of advanced age, still have a limited prognosis. In addition to cytotoxic chemotherapies, hypomethylating agents such as decitabine (5-aza-2'-deoxycytidine) and azacitidine (5-azacytidine), have been approved during the past decade and represent a very important option for the treatment of MDS today. Due to their lower toxicity compared to conventional chemotherapy, hypomethylating agents are often a safe and feasible alternative also for frail patients. Decitabine has been shown to be active in numerous studies including International Prognostic Scoring System (IPSS) intermediate-1 to high risk patients, in secondary acute myeloid leukemia (AML) arising from MDS, and in MDS with poor-risk cytogenetics. Furthermore, decitabine has been studied in the allograft setting and in combination treatment regimens, and may play a role in epigenetic "priming" before conventional chemotherapy. This review summarizes the results of clinical trials and experiences with decitabine not only in first-line and single-agent treatment regimens but also as second-line treatment after prior treatment failure, in the context of the allograft setting and as part of combination treatment regimens.Seminars in Hematology 10/2012; 49(4):330-41. · 3.99 Impact Factor -
Article: Deregulated Expression of EVI1 Defines a Poor Prognostic Subset of MLL-Rearranged Acute Myeloid Leukemias: A Study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group.
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ABSTRACT: PURPOSETo evaluate the prognostic value of ecotropic viral integration 1 gene (EVI1) overexpression in acute myeloid leukemia (AML) with MLL gene rearrangements. PATIENTS AND METHODS We identified 286 patients with AML with t(11q23) enrolled onto German-Austrian Acute Myeloid Leukemia Study Group and Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group prospective treatment trials. Material was available from 177 AML patients for EVI1 expression analysis. RESULTS: t(9;11)(p22;q23) (44.8%), t(6;11)(q27;q23) (14.7%), and t(v;11q23) (40.5%). EVI1 overexpression (EVI1(+)) was found in 45.8% of all patients with t(11q23), with t(6;11) showing the highest frequency (83.9%), followed by t(9;11) at 40.0%, and t(v;11q23) at 34.8%. Concurrent gene mutations were rare or absent in all three subgroups. Within all t(11q23) AMLs, EVI1(+) was the sole prognostic factor, predicting for inferior overall survival (OS; hazard ratio [HR], 2.06; P = .003), relapse-free survival (HR, 2.28; P = .002), and event-free survival (HR, 1.79; P = .009). EVI1(+) AMLs with t(11q23) in first complete remission (CR) had a significantly better outcome after allogeneic transplantation compared with other consolidation therapies (5-year OS, 54.7% v 0%; Mantel-Byar, P = .0006). EVI1(-) t(9;11) AMLs had lower WBC counts, more commonly FAB M5 morphology, and frequently had additional trisomy 8 (39.6%; P < .001). Among t(9;11) AMLs, EVI1(+) again was the sole independent adverse prognostic factor for survival. CONCLUSION Deregulated EVI1 expression defines poor prognostic subsets among AML with t(11q23) and AML with t(9;11)(p22;q23). Patients with EVI1(+) MLL-rearranged AML seem to benefit from allogeneic transplantation in first CR.Journal of Clinical Oncology 09/2012; · 18.37 Impact Factor -
Article: Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome.
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ABSTRACT: Background. Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define each older patient's best treatment. Design and Methods. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables. 195 patients ≥60 years with myelodysplastic syndromes/acute myeloid leukemia were assessed, grouped according to treatment intensity. The assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Results. Patients with a median age of 71 years (60-87) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count ≥20%. In 107 patients treated non-intensively activities of daily living<100 (Hazard Ratio:2.94), Karnofsky Index<80 (Hazard Ratio:2.34) and quality of life/fatigue≥50 (Hazard Ratio:1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (Hazard Ratio: 9.36). Conclusions. In-depth evaluation of older patients prior to individual treatment allocation is feasible and adds information to standard assessment. Patients ≥60 years with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index of <80%, quality of life/fatigue≥50 are likely to have poor outcomes.Haematologica 08/2012; · 6.42 Impact Factor -
Article: HDAC6 as a target for antileukemic drugs in acute myeloid leukemia.
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ABSTRACT: Inhibition of histone deacetylases (HDACs) by drugs such as vorinostat or depsipeptide has become treatment strategy under study in acute myeloid leukemia. Most preclinically and clinically investigated HDACi target classes I, II and IV, but only few are selective in inhibiting specific HDACs. Here we analyzed the in vitro antileukemic activity of three novel hydroxamate derivatives, the pan-HDAC-inhibitors ST13, ST34 and the known HDAC6 inhibitor ST80, treating leukemia cell lines HL60, Kasumi-1, NB-4, THP-1, K562, U937, Jurkat as well as primary AML blasts. In cell lines all three compounds exerted a strong growth-inhibitory effect at low micromolar concentrations. ST13 increased acetylation of H3, H4 and α-tubulin, while ST34 preferentially acetylated histones H3 and H4. Interestingly, ST80 preferentially induced α-tubulin acetylation at low micromolar doses, confirming a selective inhibition of HDAC6 by ST80 in leukemic cells. These observations were also confirmed in primary AML blasts cultured ex vivo. Growth-inhibition by ST80 was independent of pre-treatment HDAC6 protein expression and in contrast to ST13 and ST34, ST80 did not result in induction of p21/WAF. Immunofluorescence imaging confirmed that ST80 treatment both increased the abundance and resulted in unilateral local accumulation of acetylated α-tubulin. In conclusion, the three novel HDACi show potent antileukemic activity in myeloid cell lines and primary AML blasts at low micromolar concentrations. Preferential acetylation of α-tubulin implies that ST80 might exert its antileukemic effect not through histone reacetylation but rather through inhibition of HDAC6.Leukemia research 03/2012; 36(8):1055-62. · 2.36 Impact Factor -
Article: Aggressive plasmablastic lymphoproliferation complicated by hemophagocytic syndrome 12 years after heart transplant.
Leukemia & lymphoma 02/2012; 53(9):1845-8. · 2.40 Impact Factor -
Article: New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge.
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ABSTRACT: The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.Journal of Clinical Oncology 02/2012; 30(8):820-9. · 18.37 Impact Factor -
Article: TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.
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ABSTRACT: To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.Blood 12/2011; 119(9):2114-21. · 9.90 Impact Factor -
Article: A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy.
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ABSTRACT: The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20-30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts. To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m(2) total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1-19) with a lower dose of decitabine (20 mg/m(2)) infused over 1 hour on 3 consecutive days every 4-6 weeks. The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic. Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.Haematologica 11/2011; 97(3):393-401. · 6.42 Impact Factor -
Article: Immune response as a possible mechanism of long-lasting disease control in spontaneous remission of MLL/AF9-positive acute myeloid leukemia.
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ABSTRACT: Spontaneous complete remission (CR) is a rare, poorly understood phenomenon in acute myeloid leukemia (AML). We describe the 10-year follow-up of a patient with MLL-AF9-positive AML (Müller et al. Eur J Haematol 73:62-66, 2004), including ex vivo antileukemic immune responses which may contribute to the long-lasting spontaneous CR (tantamount to cure). We could demonstrate strong in vitro cytotoxic activity mediated by the patient's serum (cryopreserved at diagnosis 2001) against myeloid cell lines. We also addressed cellular cytotoxic activity against myeloid leukemia cells. When the patient's natural killer (NK) cells (obtained in 2007) were tested against the K562 cell line, upregulation of CD107 occurred, implying that long-term CR in this patient could be due to NK cell-mediated disease control.Annals of Hematology 09/2011; 91(1):27-32. · 2.62 Impact Factor -
Article: Quantitative analyses of DAPK1 methylation in AML and MDS.
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ABSTRACT: Aberrant DNA methylation and concomitant transcriptional silencing of death-associated protein kinase 1 (DAPK1) have been demonstrated to be key pathogenic events in chronic lymphocytic leukemia (CLL). In acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), however, the presence of elevated DNA methylation levels has been a matter of continued controversy. Several studies demonstrated highly variable frequencies of DAPK1 promoter methylation by the use of methylation-specific PCR (MSP). By quantitative high-resolution assessment, we demonstrate that aberrant DNA methylation is an extremely rare event in this region. We observed elevated levels just in one out of 246 (0.4%) AML patients, all 42 MDS patients were unmethylated. In conclusion, we present a refined DAPK1 methylation analysis in a large representative patient cohort of AML and MDS patients proofing almost complete absence of elevated DNA methylation. Our results highlight the importance of quantitative measurements for translational research questions on primary patient specimens, particularly.International Journal of Cancer 09/2011; 131(2):E138-42. · 5.44 Impact Factor -
Article: A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q.
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ABSTRACT: This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥ 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ≥ 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as #NCT00179621.Blood 07/2011; 118(14):3765-76. · 9.90 Impact Factor -
Article: Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia.
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ABSTRACT: To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.Journal of Clinical Oncology 06/2011; 29(21):2889-96. · 18.37 Impact Factor -
Article: Regulation of the adaptor molecule LAT2, an in vivo target gene of AML1/ETO (RUNX1/RUNX1T1), during myeloid differentiation.
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ABSTRACT: The leukaemia-specific fusion oncoprotein RUNX1/RUNX1T1 (AML1/ETO), resulting from the chromosomal translocation (8;21) in acute myeloid leukaemia (AML), imposes a striking genotype-phenotype relationship upon this distinct subtype of AML, which is mediated by multiple, co-ordinate downstream effects induced by this chimeric transcription factor. We previously identified the LAT2 gene, encoding the adaptor molecule LAT2 (NTAL, LAB), which is phosphorylated by KIT and has a role in mast cell and B-cell activation, as a target of the repressor activity of RUNX1/RUNX1T1. These results were confirmed and extended by demonstrating downregulation of the LAT2 protein in response to conditional RUNX1/RUNX1T1 expression, and its absence in primary AML with the t(8;21). In contrast, in a cohort of 43 AML patients, higher levels of LAT2 were associated with myelomonocytic features. Differentiation of HL-60 and NB4 cells towards granulocytes by all trans-retinoic acid (ATRA) resulted in downregulation of LAT2; conversely, it was upregulated during phorbol ester-induced monocytic differentiation of HL-60 cells. Forced expression of LAT2 in Kasumi-1 cells resulted in a striking block of ATRA- and phorbol ester-induced differentiation, implicating disturbances of the graded expression of this adaptor molecule in the maturation block of myeloid leukaemia cells.British Journal of Haematology 06/2011; 153(5):612-22. · 4.94 Impact Factor -
Article: Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group.
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ABSTRACT: To compare low-dose decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy. Two-hundred thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m(2)) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles. OS prolongation with decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) -free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters. Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.Journal of Clinical Oncology 05/2011; 29(15):1987-96. · 18.37 Impact Factor
Top co-authors
Top Journals
- Journal of Clinical Oncology (11)
- Blood (6)
- Leukemia Research (6)
- Annals of Hematology (6)
- Leukemia research (6)
Institutions
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2012
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Medizinische Hochschule Hannover
Hannover, Lower Saxony, Germany -
Deutsches Krebsforschungszentrum
Heidelberg, Baden-Wuerttemberg, Germany
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1999–2012
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Universitätsklinikum Freiburg
Freiburg, Lower Saxony, Germany
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2002–2011
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Universität Freiburg
- • Department of Internal Medicine
- • Department of Hematology
Freiburg, Lower Saxony, Germany
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