L Kanz

Universitätsklinikum Tübingen, Tübingen, Baden-Württemberg, Germany

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Publications (549)3051.8 Total impact

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    ABSTRACT: Insufficient production of leukocytes, thrombocytes and erythrocytes after allogeneic peripheral blood stem cell transplantation (PBSCT) represents a life-threatening complication. In 20 adult patients with poor graft function (PGF defined as transfusion-dependent platelet counts <20,000/µl, or leukocytes <1500/µl, or transfusion-dependent anemia) and variable causes of PGF after allogeneic PBSCT, immunomagnetically selected CD34(+) stem cell boosts (SCB) from matched unrelated (n = 8), mismatched unrelated (n = 11) or haploidentical (n = 1) donors were applied without prior conditioning. Patients received a median of 4.6 × 10(6) CD34(+) cells per kilogram bodyweight (1.9-9.1 × 10(6)) and low T cell numbers (median 0.2 × 10(4), range 0.04-0.6 × 10(4)). All patients showed responses in at least one hematopoietic lineage. Engraftment for platelets, leukocytes and hemoglobin was 88, 88 and 100 % after a median of 14, 13 and 18 days, respectively. With regard to the complete cohort, 90 % (n = 18) showed an increase in platelets (median 76,500/µl, range -7000 to 223,000/µl), 95 % (n = 19) had an increase in leukocytes (median 3110/µl, range 150-13,740/µl) and 90 % (n = 18) improved with regard to hemoglobin (median 1.9 g/dl, range -0.9 to 5.1 g/dl). Due to effective T cell depletion, only one patient developed graft versus host disease (GvHD, grade III) after SCB. Patients were followed for a median of 7.5 months (1-74 months) with 11 patients being alive and disease free with normalized peripheral blood counts at the end of follow-up. CD34(+)-selected SCB are safe and effective and can durably improve PGF even in patients receiving grafts from unrelated matched or mismatched donors with low incidence of GvHD.
    Journal of Cancer Research and Clinical Oncology 08/2015; DOI:10.1007/s00432-015-2027-x · 3.01 Impact Factor
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    ABSTRACT: Direct analysis of HLA presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here we present a systematic and comparative study of the HLA class I and II presented, non-mutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared to normal B cells, excluding relevant HLA down-regulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma-specificity. However, unsupervised analysis of our extensive HLA ligand dataset delineated a panel of 58 highly specific myeloma-associated antigens -including MMSET- which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, pre-existing CD8(+) T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naïve myeloma patients. Together, our results serve to guide antigen selection for T-cell based immunotherapy of MM. Copyright © 2015 American Society of Hematology.
    Blood 07/2015; DOI:10.1182/blood-2015-04-640532 · 10.43 Impact Factor
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    ABSTRACT: Tumor necrosis factor (TNF) receptor family members play a key role in the regulation of biological functions such as differentiation, proliferation and apoptosis of various cell types. We studied co-expression profiles of death receptors from the TNF family [TNF-related apoptosis-inducing ligand receptor (TRAILR) 1 to 3, TNF receptor 1 (TNFR1) and FAS receptor (FAS)] on peripheral blood blasts from 46 patients with acute myeloid leukemia (AML) at first diagnosis by flow cytometry and correlated the obtained specific fluorescence indices (SFI) with morphological, cytogenetic and clinical parameters. We found that the expression of TRAILR2 and R3 was significantly increased in unfavorable risk groups, according to the National Comprehensive Cancer Network. Additionally, cut-off analyses for TRAILR2 and TNFR1 showed significantly shorter overall survival, earlier disease onset, higher proportions of cases with unfavorable prognosis and higher probability of relapse when SFIs were above the established cut-off. We demonstrate that high co-expression of death receptors on blasts is an independent predictor of poor prognosis in AML. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    Anticancer research 07/2015; 35(7):4043-52. · 1.87 Impact Factor
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    ABSTRACT: Stage Specific Embryonic Antigen-4 (SSEA-4) is a glycosphingolipid, which is overexpressed in some cancers and has been linked to disease progression. However, little is known about the functions of SSEA-4 and the characteristics of SSEA-4 expressing tumor cells. Our studies identified SSEA-4 expression on a subpopulation of cells in many solid tumor cell lines but not in leukemic cell lines. FACS sorted SSEA-4(+) prostate cancer cells formed fibroblast-like colonies with limited cell-cell contacts whereas SSEA-4(-) cells formed cobblestone-like epithelial colonies. Only colonies derived from SSEA-4(+) cells were enriched for pluripotent embryonic stem cell markers. Moreover, major epithelial cell associated markers Claudin-7, E-Cadherin, ESRP1 and GRHL2 were downregulated in the SSEA-4(+) fraction of DU145 and HCT-116 cells. Similar to cell lines, SSEA-4(+) primary prostate tumor cells also showed downregulation of epithelial cell associated markers. In addition, they showed upregulation of epithelial-to-mesenchymal transition as well as mesenchymal markers. Furthermore, SSEA-4(+) cells escape from adhesive colonies spontaneously and form invadopodia-like migratory structures, in which SSEA-4, cortactin, as well as active pPI3K, pAkt and pSrc are enriched and colocalized. Finally, SSEA-4(+) cells displayed strong tumorigenic ability and stable knockdown of SSEA-4 synthesis resulted in decreased cellular adhesion to different extracellular matrices. In conclusion, we introduce SSEA-4 as a novel marker to identify heterogeneous, invasive subpopulations of tumor cells. Moreover, increased cell-surface SSEA-4 expression is associated with the loss of cell-cell interactions and the gain of a migratory phenotype, suggesting an important role of SSEA-4 in cancer invasion by influencing cellular adhesion to extracellular matrix. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Glycobiology 05/2015; 25(8). DOI:10.1093/glycob/cwv032 · 3.14 Impact Factor
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    ABSTRACT: Medical history and clinical course: A 42-year-old patient with hairy cell leukemia had been treated for 3 years by a hematologist in private practice. Initially the patient received 1 course of cladribine upon which the disease went into complete remission. 6 weeks ago a relapse was diagnosed and combination therapy with cladibrin and rituximab was initiated. Now the patient presented to the emergency room with shortness of breath and pain when breathing. Investigations, treatment and course: In the chest x-ray, patchy infiltrates and pleural effusions were found on both sides. The subsequently performed computed tomography showed bilateral compactions with an Halo suspicious for fungal infiltrates. Upon admission to the hospital, an empirical antibiotic therapy with clarithromycin and piperacillin/tazobactam was initiated, which was later escalated to meropenem and linezolid. Additionally, an antifungal therapy with voriconazole was started and later switched to liposomal amphotericin B. At his admission, a positive aspergillus antigen could be detected in the microbiological laboratory. Under antimycotic treatment the aspergillus antigen was repeatedly negative. The patient presented with pronounced cytopenias and after a switch of therapy to vemurafenib and filgrastim, the hematopoiesis could only be stimulated insufficiently. The patient was transferred to the intensive care unit three days after admission with severe respiratory failure. He died on day 8 after admission. Autopsy and diagnosis: Diagnosis was consistent with relapse of hairy cell leukemia with positive BRAF mutation and a bone marrow infiltration > 80 %. Autopsy revealed a significant hepato-splenomegaly, a lack of erythro-, granulo- and thrombopoiesis. Clots interspersed with fungal hyphae were found in both lungs and an infarction of the spleen with evidence of fungal hyphae was detected. The cultural findings post mortem on yeast or mold were negative. Conclusion: Patients with refractory hairy cell leukemia and prolonged neutropenia are at increased risk for systemic fungal infections. Therefore, prohylactic antimycotic therapy should be considered early in this group of patients. The therapeutic approach of vemurafenib in treatment-refractory hairy cell leukemia is promising and offers an additional treatment option. In the present case, the patient could unfortunately not be stabilized due to the septic complications. © Georg Thieme Verlag KG Stuttgart · New York.
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    ABSTRACT: Tyrosine kinase inhibitors (TKI) have changed the natural course of CML. With the advent of 2nd generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM)..1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years 965 patients (64%) still received IM. At 10-years, progression-free survival was 82%, overall-survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% MMR and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). 8-year probabilities of adverse drug reactions (ADR) were 76%, of grade 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800mg and IM 400mg + IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.Leukemia accepted article preview online, 13 February 2015. doi:10.1038/leu.2015.36.
    Leukemia 02/2015; 29(5). DOI:10.1038/leu.2015.36 · 9.38 Impact Factor
  • Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544627
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    ABSTRACT: Reduced intensity conditioning regimens lead to an increasing use of allogeneic hematopoietic cell transplantation (HCT) in elderly patients. We retrospectively analyzed 151 patients aged ⩾60 receiving allogeneic HCT 2000-2012 at our center. Median age was 66 years. Kaplan-Meier estimated 3-year OS was 42% with a median follow-up of 38 months. Cumulative incidences of progression and non-relapse mortality after 3 years were 38 and 24%. OS was better in the group of patients >65 years with a Kaplan-Meier estimated OS of 50% vs 34%, P=0.060. We observed a significant influence of donor age (<50 years: 53% vs >50 years: 30%, P=0.017) and gender match (matched: 57% vs mismatched: 32%, P=0.007) on outcome. The use of a matched related donor was inferior compared with a matched or mismatched unrelated donor (19% vs 47%, P=0.015). On multivariate analysis there was an increased hazard ratio for a non-gender-matched HLA-matched-related donor (hazard ratio 3.23, 95% confidence interval 1.55-6.74, P=0.002). Age had no significant impact on OS (P=0.414). In conclusion, the data suggest that older age alone has no negative impact on the outcome of allogeneic HCT. Transplant decision should be tailored to disease risk and patient performance status rather than age.Bone Marrow Transplantation advance online publication, 19 January 2015; doi:10.1038/bmt.2014.292.
    Bone Marrow Transplantation 01/2015; 50(3). DOI:10.1038/bmt.2014.292 · 3.47 Impact Factor
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    ABSTRACT: The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.
    Proceedings of the National Academy of Sciences 12/2014; 112(2). DOI:10.1073/pnas.1416389112 · 9.81 Impact Factor
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    ABSTRACT: Background Transfusion of ABO major–incompatible red blood cells (RBCs) can activate the complement system and can cause severe and even lethal acute hemolytic reactions. The activation of the complement system with formation of C3a and C5a (anaphylatoxins) and the release of hemoglobin from the lysed RBCs are thought to mediate clinical signs like fever, hypotension, pain, and acute renal failure. Therapeutic inhibition of the complement cascade in case of ABO-incompatible RBC transfusion would be desirable to ameliorate the signs and symptoms and to improve the outcome of the reaction.Study Design and MethodsA patient with blood group B was erroneously transfused with a unit of group A2 RBCs. Within 1 hour after transfusion she received eculizumab, a monoclonal antibody that binds to the complement component C5 and blocks its cleavage. Clinical and immunohematologic observations are reported here.ResultsHemoglobinemia and hemoglobinuria were present for several hours after transfusion, but she developed no hypotension, no renal failure, and no disseminated intravascular coagulation. As shown by flow cytometry, group A cells survived in the peripheral blood for more than 75 days. No immunoglobulin G was detectable by column agglutination technique on these cells.ConclusionA low isoagglutinin titer and blood group A2 of the erroneously transfused cells most likely were the reason for the absence of clinical signs during and immediately after the ABO-incompatible transfusion. In the further course, eculizumab successfully protected the incompatible RBCs from hemolysis for several weeks.
    Transfusion 10/2014; 55(3). DOI:10.1111/trf.12882 · 3.57 Impact Factor
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    ABSTRACT: The impact of intraocular involvement (IOL) in primary CNS lymphoma (PCNSL) has not been sufficiently evaluated. Here, we present the analysis of IOL in the only completed randomized phase III trial in PCNSL. The G-PCNSL-SG1 study evaluated the role of whole-brain radiotherapy in primary therapy of PCNSL. Data of the 526 eligible study patients were checked, and clinical characteristics, therapy, and outcome of patients with IOL diagnosed at study inclusion were analyzed. Ophthalmologic examination at study inclusion was performed in 297 patients (56.5 %) of whom IOL was diagnosed in 19 (6.4 %). Clinical characteristics did not significantly differ between patients with IOL (IOL+) and those without (IOL-). The median progression-free survival (PFS) in the IOL+ group was 3.5 months (95 % CI 0.0-7.07) as compared to 8.3 months (95 % CI 4.78-11.78) in the IOL- group (P = 0.004), the median overall survival (OS) was 13.2 months (95 % CI 0.86-25.62) and 20.5 months (95 % CI 15.56-25.5), respectively (P = 0.155). In multivariate analysis, a significantly inferior PFS and OS for IOL+ patients were found. IOL at diagnosis of PCNSL was an independent negative prognostic indicator for PFS and OS in this analysis.
    Annals of Hematology 09/2014; 94(3). DOI:10.1007/s00277-014-2212-z · 2.40 Impact Factor
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    ABSTRACT: Diagnosis of chronic myelomonocytic leukemia (CMML) is based on a combination of clinical, laboratory and morphological parameters, including persistent peripheral blood (PB) monocytosis. Recently, mutations of serine/arginine-rich splicing factor 2 (SRSF2) have been identified in 40-50% of CMML and occasionally in other myeloid disorders. In this study, we established a robust assay for the detection of SRSF2 mutations in decalcified, paraffin-embedded bone marrow (BM) biopsies and investigated its diagnostic utility. BM biopsies of 78 patients with myeloid neoplasms, including 36 CMML, 22 myelodysplastic syndromes (MDS) and 20 Ph- myeloproliferative neoplasms (MPN) were analyzed. The region around hotspot P95 in exon 1 of SRSF2 was amplified and bidirectionally sequenced. In addition, a restriction fragment length polymorphism (RFLP) analysis was established. The JAK2 V617F mutation was investigated by allele-specific PCR. SRSF2 mutations were identified in 16/36 (44%) CMML, including 1/3 cases with associated systemic mastocytosis, 4/20 (20%) Ph- MPN, and 1/22 (4.5%) MDS. RFLP analysis detected all mutations with exception of a single P95A. Of note, two cases of JAK2 V617F + primary myelofibrosis (PMF) with SRSF2 mutation initially were diagnosed as CMML based on significant PB monocytosis. In CMML, no correlation with histopathology and/or clinical parameters was observed, but SRSF2 mutations were associated with normal karyotype (p < 0.001). In summary, SRSF2 mutations are frequent in CMML and a useful diagnostic feature demonstrable in BM biopsies, allowing a definitive diagnosis for cases with minimal dysplasia and normal karyotype. The role of SRSF2 mutations in cases with hybrid features between PMF and CMML needs further investigation.
    Human pathology 09/2014; 45(12). DOI:10.1016/j.humpath.2014.08.014 · 2.81 Impact Factor
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    ABSTRACT: Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented HLA ligands, termed the HLA ligandome. In this study we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML) -associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 ligandome-derived tumor-associated antigens (LiTAAs) and 341 corresponding HLA ligands (LiTAPs) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by IFN-γ ELISPOT and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T cell epitopes and potentially synergistic embedded HLA ligands allowing for complementation of a multi-peptide vaccine for the immunotherapy of AML.Leukemia accepted article preview online, 5 August 2014; doi:10.1038/leu.2014.233.
    Leukemia 08/2014; 29(3). DOI:10.1038/leu.2014.233 · 9.38 Impact Factor
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    ABSTRACT: Lenalidomide in combination with dexamethasone is an effective and well-established treatment of relapsed or refractory multiple myeloma (rrMM) disease. Due to the scarcity of reports assessing benefit and risk of long-term lenalidomide treatment in non-selected rrMM patients, we retrospectively analysed the long-term outcome in patients with rrMM treated with lenalidomide and dexamethasone. Sixty-seven patients (pts) who were treated with lenalidomide/dexamethasone for rrMM in the approved indication from 2007 to 2011 were included in this retrospective, single-centre analysis. Kaplan-Meier survival estimates were compared between total population, patients on lenalidomide for more than 12 months (mo) and patients discontinuing therapy earlier than 12 months. Median overall survival (OS) of the total patient population was 33.2 mo. OS of pts treated beyond 12 mo was 42.9 mo compared to 20.2 mo (p = 0.027) for pts stopping lenalidomide earlier than 12 mo for other reasons than progression disease (PD). OS of pts >12 mo on lenalidomide treatment did not significantly differ between pts who had received previous autologous transplantation, allogeneic transplantation or conventional therapy. Main non-hematologic toxicities were infections of grade 3/4 in 25 % and thrombembolic events of all grades in 18 % of patients. To the best of our knowledge, this is the first report on feasibility and efficacy of long-term lenalidomide treatment in a non-selected patient cohort. OS of pts >12 mo on lenalidomide is superior when compared to pts discontinued earlier for reasons other than PD. Our data confirm the current use of lenalidomide as a continuous long-term treatment strategy.
    Annals of Hematology 07/2014; 93(12). DOI:10.1007/s00277-014-2149-2 · 2.40 Impact Factor
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    ABSTRACT: Background While paraneoplastic leukocytosis is a common phenomenon in solid tumors, extreme elevations of white blood counts (WBC) in the range of more than 100,000/μl are uncommon in patients with non-hematologic malignancies. Leukocytosis with mature neutrophils due to a granulocyte colony-stimulating factor (G-CSF) producing tumor is only seen on rare occasions. Case presentation Massive neutrophil leukocytosis of approximately 100,000/μl was diagnosed in a 57-year-old Caucasian woman with metastatic undifferentiated endometrial sarcoma. A bone marrow trephine biopsy revealed massively increased granulopoiesis, but no evidence of monoclonal myeloproliferative disease. After the primary tumor had been resected, white blood count (WBC) plummeted and went back to nearly normal levels within one week. With progressive metastatic disease, granulocyte colony-stimulating factor (G-CSF) plasma levels were found to be increased by 10-fold. White blood count (WBC) strictly correlated with tumor burden and response to chemotherapy. In the final stage of treatment resistent disease, white blood count (WBC) approximated 300,000/μl. Conclusion We report on a granulocyte colony-stimulating factor (G-CSF) secreting undifferentiated endometrial sarcoma, which was associated with extreme neutrophil counts. White blood count (WBC) were closely correlated with tumor burden and associated with an aggressive clinical course. We suggest that paraneoplastic neutrophilia represents a poor prognostic sign in soft tissue sarcoma. In patients with similar constellations, antitumor therapy must not be delayed.
    BMC Research Notes 05/2014; 7(1):313. DOI:10.1186/1756-0500-7-313
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    ABSTRACT: The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 (b2a2) and e14a2 (b3a2) on disease phenotype and outcome is still conflicting. A total of 1,105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, and Euro risk score were observed. A significant difference was found comparing white blood cells (88 vs. 65 x 109/L, p<0.001) and platelets (296 vs. 430 x 109/L, p<0.001) at diagnosis indicating a distinct disease phenotype (e13a2 vs. e14a2, respectively). No significant difference was observed regarding other hematologic features including spleen size and hematologic adverse events during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (p=0.002 for major molecular response, p<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no prediction can be made by e13a2 vs. e14a2 BCR-ABL1 transcript type at diagnosis. ClinicalTrials.gov identifier: NCT00055874 (http://clinicaltrials.gov).
    Haematologica 05/2014; 99(9). DOI:10.3324/haematol.2013.096537 · 5.87 Impact Factor
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    ABSTRACT: Early assessment of response at 3 months of tyrosine kinase inhibitor (TKI) treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, Beta-Glucuronidase (GUS) was used as reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. 301 of these were treatment-naïve at sample collection. Results: i) With regard to absolute transcript levels at diagnosis no predictive cut-off could be identified. ii) At 3 months an individual reduction of BCR-ABL transcripts to the 0.35 fold of baseline level (0.46-log reduction, i.e. roughly half-log) separated best (high-risk: 16% of patients, 5-year overall survival 83 vs 98%, HR 6.3, P=0.001). iii) At 3 months, a 6% BCR-ABL(IS) cut-off derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high-risk: 22% of pts, 5-year overall survival 85% vs. 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.Leukemia accepted article preview online, 06 May 2014; doi:10.1038/leu.2014.153.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2014; 28(10). DOI:10.1038/leu.2014.153 · 9.38 Impact Factor
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    ABSTRACT: Natural killer (NK)-cell alloreactivity after allogeneic hematopoietic cell transplantation (HCT) is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and human leukocyte antigen (HLA) class I ligands on recipient cells. We investigated the influence of donor KIR haplotype and KIR-ligand mismatch (MM) on relapse in 57 patients with hematologic malignancies receiving haploidentical HCT after reduced intensity conditioning and graft CD3/CD19 depletion. Of the 57 donors, 17 had KIR haplotype A (29.8 %) and 40 had KIR haplotype B (70.2 %). A KIR-ligand MM was found in 34 of 57 patients (59.6 %). There was no difference between donor KIR haplotypes in non-relapse mortality (NRM, p = 0.200) but had a significantly reduced incidence of relapse for patients with a haplotype B donor (p = 0.001). In particular, patients in partial remission (PR) benefited more from a haplotype B graft (p = 0.008) than patients in complete remission (CR, p = 0.297). Evaluating KIR-ligand MM cumulative incidences of relapse (p = 0.680) or NRM (p = 0.579), we found no significant difference. In conclusion, in the setting of reduced intensity conditioning (RIC) and CD3/CD19-depleted haploidentical HCT, we could not confirm the positive data with KIR-ligand MM but observed a significant lower risk of relapse with a KIR haplotype B donor.
    Annals of Hematology 04/2014; 93(9). DOI:10.1007/s00277-014-2084-2 · 2.40 Impact Factor
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    ABSTRACT: Background CRMO is a rare condition (about 1:1.000.000) with clinical signs of osteomyelitis but is without detection of any bacterial or fungal agents. Due to its inflammatory character, the missing of any known pathogen and its relapsing remitting course, CRMO is classified as an auto (?) inflammatory disease. CRMO must be seen as an exclusion diagnosis. In the past, CRMO was considered to be a disease exclusively limited to childhood. More recently, cases in adults have been described, however, there may be an increased risk of misdiagnosis Conclusions These four cases show that despite of typical clinical symptoms, imaging and histopathological findings, the diagnosis of CRMO in adults should always be questioned. This is of utmost importance not only before starting immunosuppressive treatment, but also in case of insufficient efficacy of therapy. The major differential diagnosis of CRMO in adulthood is intraosseous lymphoma, which probably as paraneoplastic phenomenon histopathologically may mimick CRMO. The signs of this autoinflammatory disease are local pain, systemic inflammatory sings (B-symptoms), laboratory findings of inflammation with elevated C-reactive protein level, erythrocyte sedimentation rate, peripheral leukocytes and ferritin level. Furthermore the MRI that reveals the inflammation and/or lesions, plain radiographic findings with osteolytic, sclerotic, or a mixed lytic-sclerotic lesion. All these are also typical of lymphoma, not only of CRMO and unspecific. Disclosure of Interest None Declared.
    Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):698-698. DOI:10.1136/annrheumdis-2012-eular.1058 · 10.38 Impact Factor
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    ABSTRACT: Background Autologous stem cell transplantation (aSCT) has proven to be effective in systemic sclerosis (Ssc). Cyclophosphamide (CYC) is one cornerstone for conditioning treatment but is known to be cardiotoxic. Two case reports describe the successful use of thiotepa1,2. Objectives To find an alternative, less cardiotoxic conditioning regimen Methods Retrospective analysis of 6 patients with Ssc who received aSCT using a conditioning therapy with a reduced dose of CYC (2x50mg/kg bodyweight) + thiotepa (2x5mg/kg bodyweight) + rabbit antithymocyte globulin. Modified Rodnan skin score (mRSS), as well as CT histography – measuring median lung density (MLD, Hounsfield units) as well as total lung volume and high attenuation value (HAV) were used to assess efficacy after 6 and 12 months. For safety parameters we assessed the time to engraftment (>500 neutrophils and >20.000 thrombocytes/µl), severe complications as well as troponin I (normal or elevated) and echocardiography (left ventricular function and systolic pulmonary arterial pressure (PAPsys >30mmHg = pathologic). Results Four male and 2 female patients with a median age of 41years (19-57) and a disease duration of 1.8 years (0.5-4.5) were transplanted for progressive Ssc despite CYC pulse pre-treatment. Indication for the alternative treatment regimen were biopsy proven myocardial fibrosis in all patients plus pathologic 24h-ECG (n=4), echocardiography (n=2) or cardio MRI (n=2). All patients have had elevated troponin values in the past and received an implantable cardioverter defibrillator in preparation for aSCT. The median time to regeneration was 21 and 20 days for neutrophils and thrombocytes. Two patients, who were transplanted at the same day, experienced a severe aspergillus pneumonia which was successfully treated with antimycotic therapy. No transplant-related mortality was observed. The median mRSS significantly reduced from 26.5 to 18 (p=0.028) and 17.5 at month 6 and 12, respectively. Using lung CT histography, MLD as well as total lung volume and HAV improved during the first year. One patient, initially having responded, experienced a severe progression of skin thickening and PapSys after 9 months. He died 1.6 years after aSCT due to progressive disease. Another patient had a mild alveolitis after 1.5 years with a which was successfully treated with 4 pulses CYC. All other patients show an ongoing response to treatment without sign of progression. This leads to a progression free survival rate of 66.6% during the median follow up period of 1.4 (0.5-3.8) years. In none of the patients elevation of troponin or reduction of left ventricular function could be assessed during the median follow up period of 1.4 years. Conclusions A conditioning regimen with a reduced CYC dose and partial substitution by thiotepa is feasible and seems to be effective. The two cases of aspergillus infections must be watched carefully; interestingly they appeared during the same time, so air contamination can be discussed. Our preliminary experiences led to our currently recruiting protocol with the use of this regimen in patients with Ssc and cardiac involvement. References Disclosure of Interest: None Declared
    Rheumatology (Oxford, England) 01/2014; 72(Suppl 3). DOI:10.1093/rheumatology/ket464 · 4.44 Impact Factor

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17k Citations
3,051.80 Total Impact Points


  • 1997–2015
    • Universitätsklinikum Tübingen
      • • Department of Medicine
      • • Internal Medicine II - Oncology, haematology, clinical immunology, rheumatology and pneumology
      • • Abteilung Hämatologie
      Tübingen, Baden-Württemberg, Germany
    • Hohenheim University
      Stuttgart, Baden-Württemberg, Germany
    • Universitätsklinikum Freiburg
      • Department of Rehabilitation and Preventive Sport Medicine
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1995–2015
    • University of Tuebingen
      • • Centre for Geriatric Medicine
      • • Eye Hospital
      • • Department of Internal Medicine
      Tübingen, Baden-Württemberg, Germany
  • 2014
    • Hospital Universitario Miguel Servet
      Caesaraugusta, Aragon, Spain
  • 2007
    • University of Hamburg
      Hamburg, Hamburg, Germany
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 1997–2006
    • Goethe-Universität Frankfurt am Main
      • • Abteilung für Hämatologie/Onkologie
      • • Institut für Medizinische Virologie
      Frankfurt, Hesse, Germany
  • 2005
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 2000–2005
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 2000–2004
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 1996–2003
    • Martin Luther University Halle-Wittenberg
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2001
    • Haematology Oncology Practice Altona
      Hamburg, Hamburg, Germany
  • 1999
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 1998
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1982–1994
    • University of Freiburg
      • Institute of Forensic Medicine
      Freiburg, Baden-Württemberg, Germany