Wolfgang Hiddemann

Ludwig-Maximilians-University of Munich, München, Bavaria, Germany

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Publications (320)2104.96 Total impact

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    ABSTRACT: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Deutsche Krebshilfe, Terry Fox Research Institute. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 08/2015; 16(9). DOI:10.1016/S1470-2045(15)00169-2 · 24.69 Impact Factor
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    ABSTRACT: Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB = 30-66%, ABC = 45-57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB = 16-38%, ABC = 25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus + bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction.
    Leukemia & lymphoma 08/2015; · 2.89 Impact Factor
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    ABSTRACT: T cell function is crucial for the success of several novel immunotherapeutic strategies for the treatment of acute myeloid leukemia (AML). However, changes in phenotype and function of T cells have been described in various hematologic malignancies, mimicking T cell exhaustion known from chronic viral infections. Detailed knowledge about phenotype and function of T cells in AML patients at different stages of the disease is indispensable for optimal development and application of immunotherapeutic strategies for this disease. We used flow cytometry-based assays to characterize T cell phenotype and function in peripheral blood and bone marrow of AML patients at diagnosis, at relapse after intensive chemotherapy, and at relapse after allogeneic stem cell transplantation (SCT). Surface expression of CD244, PD-1, CD160, and TIM-3 was determined, and proliferation and production of IFN-γ, TNF-α, and IL-2 were measured. We detected similar expression of inhibitory molecules on T cells from patients at diagnosis and from age-matched healthy controls. At relapse after SCT, however, PD-1 expression was significantly increased compared to diagnosis, both on CD4(+) and CD8(+) T cells. This pattern was not associated with age and cytomegalovirus (CMV) status but with a shift towards effector memory cells in relapsed AML patients. Proliferation and cytokine production assays did not reveal functional defects in T cells of AML patients, neither at diagnosis nor at relapse. We thus conclude that T cell exhaustion does not play a major role in AML. Immunotherapeutic strategies targeting autologous T cells thus have particularly good prospects in the setting of AML.
    Journal of Hematology & Oncology 07/2015; 8(1):93. DOI:10.1186/s13045-015-0189-2 · 4.81 Impact Factor
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    ABSTRACT: The adapter protein metastasis suppressor 1 (MTSS1) is implicated as a tumor suppressor or tumor promoter, depending on the type of solid cancer. Here, we identified Mtss1 expression to be increased in AML subsets with favorable outcome, while suppressed in high risk AML patients. High expression of MTSS1 predicted better clinical outcome of patients with normal-karyotype AML. Mechanistically, MTSS1 expression was negatively regulated by FLT3-ITD signaling but enhanced by the AML1-ETO fusion protein. DNMT3B, a negative regulator of MTSS1, showed strong binding to the MTSS1 promoter in PML-RARA positive but not AML1-ETO positive cells, suggesting that AML1-ETO leads to derepression of MTSS1. Pharmacological treatment of AML cell lines carrying the FLT3-ITD mutation with the specific FLT3 inhibitor PKC-412 caused upregulation of MTSS1. Moreover, treatment of acute promyelocytic cells (APL) with all-trans retinoic acid (ATRA) increased MTSS1 mRNA levels. Taken together, our findings suggest that MTSS1 might have a context-dependent function and could act as a tumor suppressor, which is pharmacologically targetable in AML patients.
    PLoS ONE 05/2015; 10(5):e0125783. DOI:10.1371/journal.pone.0125783 · 3.23 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups.
    PLoS ONE 03/2015; 10(3):e0120925. DOI:10.1371/journal.pone.0120925 · 3.23 Impact Factor
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    ABSTRACT: Wilms Tumor-1 (WT1) expression level has long been found to be implicated in acute myeloid leukemia (AML) prognosis, though this is not reflected in current AML risk stratification. We hypothesized that a gene expression profile (GEP) associated with WT1 expression could be of prognostic value. We analyzed two publically available AML GEP series in order to identify a gene signature associated with high-WT1 expression (hi-WT1). The first, herein called Netherlands series, comprised of 524 younger adult patients who have been treated according to sequential Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON/SAKK) AML-04, 04A, 29, 32, 42, and 43 protocols (GSE14468). The second series, herein called Germany series, consisted of 562 younger and older AML patients who were treated in the German AMLCG 1999 trial (GSE37642). We identified the hi-WT1 gene sets by comparing GEP among the highest and lowest quartiles of WT1 expression in both AML studies. About 62% of the probe sets in the Netherlands hi-WT1 set were found to be common with the Germany hi-WT1 set; 97% differed in the same direction. Moreover, a high degree of correlation of the fold differences was found among the two hi-WT1 sets (r2 = 0.81, p < 10-18), collectively suggesting a biological relevance for hi-WT1 gene sets. In order to assess the prognostic implication of the hi-WT1 set, we used K-Nearest Neighborhood algorithm to generate various lists of hi-WT1 probe sets predicting event-free survival (EFS) as the favorable, and all others (dead, no remission, progressive disease/relapse) as the unfavorable events in the Netherlands series. Stepwise screening of the lists of 10 to 100 probe sets by Cox Regression identified a 16-gene subset of hi-WT1 set with distinct GEP and as the optimal predictor of overall survival (OS) and EFS in the Netherlands series. It comprised of GPR56, FAM30A, NGFRAP1, WBP5, LTK, PTP4A3, CD109, ZC3H12C, PYGB, CHIC1, HAVCR2, TMEM110, HAL, HDAC4, BLVRA, and P2RY2. In this series, the hi-WT1 cluster of patients showed lower 5y-probability of OS (10% vs 44%) and EFS (6% vs 38%) as compared to the remaining clusters. Accordingly, the hi-WT1 cluster showed shorter median OS (8.3 [CI 6.7-9.9] vs 31.3 [CI 17.1-45.5] months, P = 6 x 10-18) and EFS (4.9 [CI 3.2-6.5] vs 14.5 [CI 9.4-19.5] months, P = 3 x 10-16). Although the hi-WT1 cluster was associated with some of the cytogenetic and molecular aberrations including FLT3-ITD, it remained significant for both OS (P = 3 x 10-5) and EFS (P = 3 x 10-6) after adjustment for known AML risk factors. In order to validate our findings, we performed a supervised clustering of the Germany AML series using the 16-gene signature. The hi-WT1 cluster predicted both adverse OS and relapse-free survival (RFS) (Fig. 1), which remained statistically significant after adjustment for known AML risk factors (Table 1). The median OS was 7.1 (CI 5.7-8.5) months for the hi-WT1 cluster as compared to 20.1 (CI 15.2- 25.0) months for other cases (P = 2 x 10-13), and the median RFS was 5.8 (CI 4.8-6.8) vs 20.3 (CI 10.6-30.0) months, respectively (P = 2 x 10-11). Moreover, the rate of complete remission was significantly lower in hi-WT1 cluster as compared to other clusters (42% vs 61%, P = 2 x 10-5). The positive (PPV) and negative predictive value (NPV) of the marker for prediction of adverse OS were 90% and 34%, respectively. These values were found to be 88% and 38%, respectively, for prediction of adverse RFS. MetaCore analysis identified the Antigen Presentation by MHC-II as the most implicated biological pathway in hi-WT1 sets, with many genes downregulated in the pathway. In brief, we identified a 16-gene signature associated with WT1 expression and demonstrated its adverse and independent prognostic impact in adult AML patients. These promising results should be validated in further trials and provide new clues to the molecular mechanisms underlying WT1 regulation.
    American Society of Hematology, San Francisco; 12/2014
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    56th ASH Annual Meeting and Exposition, San Francisco; 12/2014
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    11/2014; 2(Suppl 3):P115-P115. DOI:10.1186/2051-1426-2-S3-P115
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    Journal for Immunotherapy of Cancer; 11/2014
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    ABSTRACT: This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove efficacy and feasibility of a short-intensive chemotherapy combined with the anti-CD20 antibody Rituximab. 363 patients 16 to 85 years old (median 42 yrs) were recruited in 98 centers from 8/2002 until 06/2011. Treatment consisted of 6 five-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years received a reduced regimen. Rituximab was given d -1 before each cycle and twice as maintenance, for a total of 8 doses. The complete remission rate was 88% (319/363), the overall survival (OS) at 5 years 80%, and the progression-free survival (PFS) 71%, with significant difference between adolescents (≥15-25 yrs), adults (26-55 yrs) and elderly (>55 yrs) patients with an OS of 90%, 84%, and 62%. Full treatment could be applied in 86% of the patients. Most important prognostic factors were IPI (0-2 vs. 3-5, p=0.0005), aaIPI (0-1 vs. 2-3, p=0.0001), and gender (male vs. female, p=0.004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, also in elderly patients. The study is registered to www.clinicaltrials.gov as NCT00199082.
    Blood 10/2014; 124(26). DOI:10.1182/blood-2014-03-563627 · 10.45 Impact Factor
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    ABSTRACT: Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.
    Oncotarget 10/2014; 5(23). DOI:10.18632/oncotarget.2642 · 6.36 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 · 3.23 Impact Factor
  • British Journal of Haematology 10/2014; 168(4). DOI:10.1111/bjh.13132 · 4.71 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 · 4.81 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 · 10.45 Impact Factor
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    ABSTRACT: Cyclic cytotoxic maintenance therapy can be applied to patients with AML in post-remission. We studied the immune status of AML patients in complete remission and the effect of maintenance therapy on different immune cell populations. Patients in complete remission had reduced NK, TH and Treg counts and a reduced NK activation capacity. In the course of cytotoxic maintenance therapy, NK counts further declined, while TH and Treg cells increased, with lower proliferative potential of TH cells. We conclude that immunotherapeutic approaches in post-remission have to consider reduced NK cell function and further impairment of cellular immune responses during cytotoxic therapy.
    Leukemia Research 06/2014; 38(8). DOI:10.1016/j.leukres.2014.05.014 · 2.35 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; 99(8). DOI:10.3324/haematol.2014.104133 · 5.81 Impact Factor
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    ABSTRACT: Hyperleukocytosis in AML with leukostasis is a serious life-threatening condition leading to a high early mortality which requires immediate cytoreductive therapy. Therapeutic leukapheresis is currently recommended by the American Society of Apheresis in patients with a WBC>100 G/l with signs of leukostasis, but the role of prophylactic leukapheresis before clinical signs of leukostasis occur is unclear. We retrospectively analyzed the role of leukapheresis in 52 patients (median age 60 years) with hyperleukocytotic AML with and without clinical signs of leukostasis. Since leukapheresis was performed more frequently in patients with signs of leukostasis due to the therapeutic policy in our hospital, we developed a risk score for early death within seven days after start of therapy (EDd7) to account for this selection bias and to independently measure the effect of leukapheresis on EDd7. 20 patients received leukapheresis in combination to chemotherapy compared to 32 patients who received chemotherapy only. In a multivariate logistic regression model for the estimation of the probability of EDd7 thromboplastin time and creatinine remained as independent significant parameters and were combined to create an EDd7 risk score. The effect of leukapheresis on EDd7 was evaluated in a bivariate logistic regression together with the risk score. Leukapheresis did not significantly change early mortality in all patients with a WBC≥100 G/l. Prophylactic leukapheresis in hyperleukocytotic patients with and without leukostasis did not improve early mortality in our retrospective study. Larger and prospective clinical trials are needed to validate the risk score and to further explore the role of leukapheresis in AML with hyperleukocytosis.
    PLoS ONE 04/2014; 9(4):e95062. DOI:10.1371/journal.pone.0095062 · 3.23 Impact Factor
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    ABSTRACT: Waldenström's Macroglobulinemia (WM) is an indolent lymphoma and is responsive to therapy regimens containing alkylating agents, purine analogues and rituximab if treatment becomes necessary. We initiated a multi-center phase II trial to determine the safety and efficacy of a regimen containing pentostatin, cyclophosphamide and rituximab (PER) in patients with WM. Between May 2005 and December 2010 twenty-five patients with WM were included in the study. Twenty-one patients received PER as first-line therapy. In these patients, two-year progression-free survival was 83.6% and two-year overall survival was 100%. Thirteen patients (52%) started with the rituximab maintenance therapy. In these patients, the two-year progression-free survival was 91.67% and two-year overall survival was 100%. We have provided evidence that PER is a safe and effective regimen for WM. Although rituximab maintenance therapy after PER seemed to induce a better long term outcome, this study was not powered to address this issue.
    Leukemia & lymphoma 04/2014; 56(1). DOI:10.3109/10428194.2014.911869 · 2.89 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 · 18.43 Impact Factor

Publication Stats

17k Citations
2,104.96 Total Impact Points


  • 1999–2015
    • Ludwig-Maximilians-University of Munich
      • Department of Internal Medicine II
      München, Bavaria, Germany
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 2014
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
  • 2008–2014
    • Helmholtz Zentrum München
      • Institute of Pathology
      München, Bavaria, Germany
    • University of Duisburg-Essen
      Essen, North Rhine-Westphalia, Germany
  • 2004–2014
    • Technische Universität München
      München, Bavaria, Germany
  • 2001–2014
    • University Hospital München
      München, Bavaria, Germany
    • University Hospital Regensburg
      • Klinik für Chirurgie
      Ratisbon, Bavaria, Germany
  • 2012
    • ICH Study Center
      Hamburg, Hamburg, Germany
  • 2010
    • Münchner Leukämie Labor GmbH
      München, Bavaria, Germany
  • 1982–2009
    • University of Münster
      • Department of Internal Medicine
      Muenster, North Rhine-Westphalia, Germany
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2006
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
  • 2002–2006
    • University of Cologne
      • Department of Internal Medicine
      Köln, North Rhine-Westphalia, Germany
  • 2005
    • Universitätsklinikum Münster
      • Medizinische Klinik und Poliklinik A
      Muenster, North Rhine-Westphalia, Germany
  • 2002–2003
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1996–1999
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 1998
    • Haematology Oncology Practice Altona
      Hamburg, Hamburg, Germany
    • ZIM - Zentrum Innere Medizin
      Schleisheim, Bavaria, Germany
  • 1995
    • Freie Universität Berlin
      • Institute of Veterinary Pathology
      Berlín, Berlin, Germany
    • Universitätsmedizin Göttingen
      • Department of Hematology and Oncology
      Göttingen, Lower Saxony, Germany