56 results on '"Ulf Schnetzke"'
Search Results
2. A Mosquito Bite with Devastating Complications in an Immunocompromised Patient
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Jochen J. Frietsch, Nils Winkelmann, Friederike Hunstig, Ulf Schnetzke, Friedrich J. Hammersen, Torsten Dönicke, Mark Lenz, Florian Gras, Sebastian Scholl, Andreas Hochhaus, and Inken Hilgendorf
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Aspergillus flavus ,Hematopoietic stem cell transplantation ,Mesh graft ,Phlegmon ,Very severe aplastic anemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Infectious complications such as invasive aspergillosis or infection with Stenotrophomonas maltophilia (SM) in immunocompromised patients are associated with a high mortality rate. Our report concerns a 40-year-old male newly diagnosed very severe aplastic anemia (vSAA) who in consequence of a mosquito bite was suffering from skin lesion and consecutive soft tissue phlegmon subsequent to the administration of antithymocyte globulin; a full-thickness autologous meshed skin graft successfully performed to cover skin ulcera after allogeneic stem cell transplantation (SCT). This unusual case illustrates the importance of appropriate diagnosis, anti-infective therapy and close interdisciplinary diagnostic algorithms to minimalize side effects and the selection of resistant strains and to improve patients’ outcome.
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- 2019
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3. Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance
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Maximilian Fleischmann, Mike Fischer, Ulf Schnetzke, Colin Fortner, Joanna Kirkpatrick, Florian H. Heidel, Andreas Hochhaus, and Sebastian Scholl
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AML ,FLT3-ITD ,HSP90 ,tunicamycin ,17-AAG ,VPA ,Cytology ,QH573-671 - Abstract
OBJECTIVES: Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) represent the most frequent molecular aberrations in acute myeloid leukemia (AML) and are associated with an inferior prognosis. The pattern of downstream activation by this constitutively activated receptor tyrosine kinase is influenced by the localization of FLT3-ITD depending on its glycosylation status. Different pharmacological approaches can affect FLT3-ITD-driven oncogenic pathways by the modulation of FLT3-ITD localization. AIMS: The objective of this study was to investigate the effects of N-glycosylation inhibitors (tunicamycin or 2-deoxy-D-glucose) or the histone deacetylase inhibitor valproic acid (VPA) on FLT3-ITD localization and downstream activity. We sought to determine the potential differences between the distinct FLT3-ITD variants, particularly concerning their susceptibility towards combined treatment by addressing either N-glycosylation and the heat shock protein 90 (HSP90) by 17-AAG, or by targeting the PI3K/AKT/mTOR pathway by rapamycin after treatment with VPA. METHODS: Murine Ba/F3 leukemia cell lines were stably transfected with distinct FLT3-ITD variants resulting in IL3-independent growth. These Ba/F3 FLT3-ITD cell lines or FLT3-ITD-expressing human MOLM13 cells were exposed to tunicamycin, 2-deoxy-D-glucose or VPA, and 17-AAG or rapamycin, and characterized in terms of downstream signaling by immunoblotting. FLT3 surface expression, apoptosis, and metabolic activity were analyzed by flow cytometry or an MTS assay. Proteome analysis by liquid chromatography–tandem mass spectrometry was performed to assess differential protein expression. RESULTS: The susceptibility of FLT3-ITD-expressing cells to 17-AAG after pre-treatment with tunicamycin or 2-deoxy-D-glucose was demonstrated. Importantly, in Ba/F3 cells that were stably expressing distinct FLT3-ITD variants that were located either in the juxtamembrane domain (JMD) or in the tyrosine kinase 1 domain (TKD1), response to the sequential treatments with tunicamycin and 17-AAG varied between individual FLT3-ITD motifs without dependence on the localization of the ITD. In all of the FLT3-ITD cell lines that were investigated, incubation with tunicamycin was accompanied by intracellular retention of FLT3-ITD due to the inhibition of glycosylation. In contrast, treatment of Ba/F3-FLT3-ITD cells with VPA was associated with a significant increase of FLT3-ITD surface expression depending on FLT3 protein synthesis. The allocation of FLT3 to different cellular compartments that was induced by tunicamycin, 2-deoxy-D-glucose, or VPA resulted in the activation of distinct downstream signaling pathways. Whole proteome analyses of Ba/F3 FLT3-ITD cells revealed up-regulation of the relevant chaperone proteins (e.g., calreticulin, calnexin, HSP90beta1) that are directly involved in the stabilization of FLT3-ITD or in its retention in the ER compartment. CONCLUSION: The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies.
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- 2021
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4. In Vivo Emergence of UL56 C325Y Cytomegalovirus Resistance to Letermovir in a Patient with Acute Myeloid Leukemia after Hematopoietic Cell Transplantation
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Jochen J Frietsch, Detlef Michel, Thomas Stamminger, Friederike Hunstig, Sebastian Birndt, Ulf Schnetzke, Sebastian Scholl, Andreas Hochhaus, and Inken Hilgendorf
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Cytomegalovirus ,hematopoietic stem cell transplantation ,reactivation ,letermovir ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
CMV associated tissue-invasive disease is associated with a considerable risk of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Recently, the terminase inhibitor letermovir (LMV) has been approved for prophylaxis of CMV infection in HSCT. We hereby report a 60-year-old female experiencing CMV reactivation after HSCT in a CMV seronegative donor-constellation. Due to ongoing elevated CMV viral load and drug-associated myelosuppression, which prevented ganciclovir therapy, treatment was replaced by foscarnet. Due to nephrotoxicity, foscarnet was switched to LMV. The patient developed skin GvHD and prednisolone was started. Subsequently, CMV viremia worsened despite LMV therapy. Genotyping revealed the mutation C325Y of the CMV UL56 terminase being associated with high-level resistance against LMV. Prolonged uncontrolled low-level viremia due to prednisolone treatment may have favored the selection of drug-resistant CMV. Despite the excellent toxicity profile of LMV, physicians should be aware of risk factors for the emergence of resistance.
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- 2019
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5. Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments
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Sebastian Scholl, Maximilian Fleischmann, Ulf Schnetzke, and Florian H. Heidel
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acute myeloid leukemia ,AML ,FMS-like tyrosine kinase 3 ,FLT3 ,FLT3-ITD ,FLT3-TKD ,Cytology ,QH573-671 - Abstract
Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML.
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- 2020
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6. Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia
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Mike Fischer, Ulf Schnetzke, Bärbel Spies-Weisshart, Mario Walther, Maximilian Fleischmann, Inken Hilgendorf, Andreas Hochhaus, and Sebastian Scholl
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2017
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7. Polymorphisms of Dectin-1 and TLR2 Predispose to Invasive Fungal Disease in Patients with Acute Myeloid Leukemia.
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Mike Fischer, Baerbel Spies-Weisshart, Karin Schrenk, Bernd Gruhn, Susan Wittig, Anita Glaser, Andreas Hochhaus, Sebastian Scholl, and Ulf Schnetzke
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Medicine ,Science - Abstract
Patients with acute myeloid leukemia (AML) who undergo induction chemotherapy are at high risk for invasive fungal disease (IFD). Dectin-1, a C-type lectin family member represents one of the most important pattern recognition receptors of the innate immune system and single nucleotide polymorphisms (SNPs) in the Dectin-1 gene have been associated with an increased risk of infectious complications. We sought to investigate the impact of three different Dectin-1 SNPs and one TLR2 SNP on developing IFD in 186 adult patients with newly diagnosed AML following anthracycline-based induction chemotherapy.Genotyping of Dectin-1 SNPs (rs16910526, rs3901533 and rs7309123) and TLR2 SNP (rs5743708) was performed by TaqMan method and pyrosequencing. IFD was defined according to the EORTC/MSG consensus guidelines. Multiple logistic regression analyses were applied to evaluate the association between the polymorphisms and the occurrence of pulmonary infections. Dectin-1 expression studies with SNP genotyped human monocytes were performed to elucidate susceptibility to IFD following chemotherapy.We could demonstrate that patients carrying the Dectin-1 SNP rs7309123 G/G (n = 47) or G/G and C/G (n = 133) genotype revealed a significant higher risk for developing both pneumonia in general (adjusted odds ratio (OR): 2.5; p = 0.014 and OR: 3.0, p = 0.004) and pulmonary IFD (OR: 2.6; p = 0.012 and OR: 2.4, p = 0.041, respectively). Patients carrying the TLR2 SNP rs5743708 (R753Q, GA/AA genotype, n = 12) also revealed a significantly higher susceptibility to pneumonia including IFD. Furthermore, Dectin-1 mRNA expression in human monocytes was lower following chemotherapy.To our best knowledge, this study represents the first analysis demonstrating that harbouring polymorphisms of Dectin-1 (rs7309123) or TLR2 (rs5743708) represents an independent risk factor of developing IFD in patients with AML undergoing induction chemotherapy.
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- 2016
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8. N-octanoyl dopamine, a non-hemodyanic dopamine derivative, for cell protection during hypothermic organ preservation.
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Ralf M Lösel, Ulf Schnetzke, Paul T Brinkkoetter, Hui Song, Grietje Beck, Peter Schnuelle, Simone Höger, Martin Wehling, and Benito A Yard
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Medicine ,Science - Abstract
BACKGROUND: Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects. METHODOLOGY/PRINCIPAL FINDINGS: To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects. CONCLUSIONS/SIGNIFICANCE: In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors.
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- 2010
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9. Staphylococcus intermedius infection with splenic abscesses in a patient with acute lymphoblastic leukemia
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Lisa Hauptmann, Danica Midic, Farina Eigendorff, Amer Malouhi, Bernhard Theis, Hermann Kißler, Jürgen Rödel, Florian Prims, Andreas Hochhaus, Sebastian Scholl, and Ulf Schnetzke
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Hematology ,General Medicine - Published
- 2023
10. Impact of treatment intensity on infectious complications in patients with acute myeloid leukemia
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Sebastian Scholl, Romy Tober, Ulf Schnetzke, Maximilian Fleischmann, Olaposi Yomade, Karin G Schrenk, Jakob F Hammersen, Anita Glaser, Christian Thiede, and Andreas Hochhaus
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Cancer Research ,Oncology ,hemic and lymphatic diseases ,General Medicine ,neoplasms - Abstract
Background Infectious complications reflect a major challenge in the treatment of patients with acute myeloid leukemia (AML). Both induction chemotherapy and epigenetic treatment with hypomethylating agents (HMA) are associated with severe infections, while neutropenia represents a common risk factor. Here, 220 consecutive and newly diagnosed AML patients were analyzed with respect to infectious complications dependent on treatment intensity and antifungal prophylaxis applied to these patients. Patients and methods We retrospectively analyzed 220 patients with newly diagnosed AML at a tertiary care hospital between August 2016 and December 2020. The median age of AML patients undergoing induction chemotherapy (n = 102) was 61 years (25–76 years). Patients receiving palliative AML treatment (n = 118) had a median age of 75 years (53–91 years). We assessed the occurrence of infectious complication including the classification of pulmonary invasive fungal disease (IFD) according to the EORTC/MSG criteria at diagnosis and until day 100 after initiation of AML treatment. Furthermore, admission to intensive care unit (ICU) and subsequent outcome was analyzed for both groups of AML patients, respectively. Results AML patients subsequently allocated to palliative AML treatment have a significantly higher risk of pneumonia at diagnosis compared to patients undergoing induction chemotherapy (37.3% vs. 13.7%, P P = 0.026). Furthermore, urinary tract infections are more frequent in the palliative subgroup at the time of AML diagnosis (5.1% vs. 0%, P = 0.021). Surprisingly, the incidence of pulmonary IFD is significantly lower after initiation of palliative AML treatment compared to the occurrence after induction chemotherapy (8.4% vs. 33.3%, P Aspergillus spp.-directed antifungal prophylaxis. The overall risk for infectious complications at AML diagnosis is significantly higher for palliative AML patients at diagnosis while patients undergoing induction chemotherapy have a significantly higher risk of infections after initiation of AML treatment. In addition, there is a strong correlation between the occurrence of pneumonia including atypical pneumonia and pulmonary IFD and the ECOG performance status at diagnosis in the palliative AML patient group. Analysis of intensive care unit (ICU) treatment (e.g. in case of sepsis or pneumonia) for both subgroups reveals a positive outcome in 10 of 15 patients (66.7%) with palliative AML treatment and in 15 of 18 patients (83.3%) receiving induction chemotherapy. Importantly, the presence of infections and the ECOG performance status at diagnosis significantly correlate with the overall survival (OS) of palliative AML patients (315 days w/o infection vs. 69 days with infection, P 0.0049 and 353 days for ECOG 2, P Conclusion The risk and the pattern of infectious complications at diagnosis and after initiation of AML therapy depends on age, ECOG performance status and subsequent treatment intensity. A comprehensive diagnostic work-up for identification of pulmonary IFD is indispensable for effective treatment of pneumonia in AML patients. The presence of infectious complications at diagnosis contributes to an inferior outcome in elderly AML patients.
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- 2022
11. Treosulfan plus fludarabine versus TEAM as conditioning treatment before autologous stem cell transplantation for B-cell Non-Hodgkin lymphoma
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Jochen J. Frietsch, Jenny Miethke, Paul Linke, Carl C. Crodel, Ulf Schnetzke, Sebastian Scholl, Andreas Hochhaus, and Inken Hilgendorf
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Transplantation ,Transplantation Conditioning ,Lymphoma, Non-Hodgkin ,Hematopoietic Stem Cell Transplantation ,Humans ,Hematology ,Busulfan ,Transplantation, Autologous ,Vidarabine ,Aged ,Retrospective Studies - Abstract
Conditioning with treosulfan and fludarabine (Treo/Flu) has been proven to be feasible and efficient in several types of malignancies before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Given its favorable reduced toxicity profile, we introduced Treo/Flu as conditioning before autologous HSCT (auto-HSCT) in patients with B-cell Non-Hodgkin lymphoma (NHL). The aim of this study was to evaluate the efficacy and safety of Treo/Flu in comparison to TEAM. Fifty-seven patients with NHL received auto-HSCT after conditioning with either Treo/Flu (n = 22) or TEAM (n = 35). All patients achieved sustained engraftment. PFS, EFS and OS were not significant in both groups. Of note is that patients in the Treo/Flu group were less dependent on thrombocyte transfusions (p = 0.0082), significantly older (in median 11 years, p p = 0.0105), mucositis and stomatitis (p
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- 2022
12. Ziele und Optionen der palliativen Therapie der akuten myeloischen Leukämie
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Maximilian Fleischmann, Ulf Schnetzke, Andreas Hochhaus, and Sebastian Scholl
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- 2022
13. Outcome of patients with relapsed or refractory acute myeloid leukemia treated with Mito-FLAG salvage chemotherapy
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Karin G. Schrenk, Jochen J. Frietsch, Andreas Hochhaus, Ulf Schnetzke, Regina Mühleck, Anita Glaser, Inken Hilgendorf, Jakob Hammersen, Sebastian Scholl, Herbert G. Sayer, and Maximilian Fleischmann
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Salvage therapy ,Hematopoietic stem cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,Humans ,Medicine ,Salvage Therapy ,Mitoxantrone ,business.industry ,Remission Induction ,Cytarabine ,Myeloid leukemia ,General Medicine ,Prognosis ,Fludarabine ,Granulocyte colony-stimulating factor ,Leukemia, Myeloid, Acute ,Treatment Outcome ,FLAG (chemotherapy) ,business ,Vidarabine ,medicine.drug - Abstract
Purpose Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML. Materials and methods Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile. Results Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5–25.4) months vs 3 (95% CI 1.7–4.3) months (p Conclusion The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown.
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- 2021
14. Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience
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Peter, Dreger, Udo, Holtick, Marion, Subklewe, Bastian, von Tresckow, Francis, Ayuk, Eva, Wagner, Gerald, Wulf, Reinhardt, Marks, Olaf, Penack, Ulf, Schnetzke, Christian, Koenecke, Malte, von Bonin, Matthias, Stelljes, Bertram, Glass, Claudia D, Baldus, Vladan, Vucinic, Dimitrios, Mougiakakos, Max, Topp, Roland, Schroers, Daniel, Wolff, Simone, Thomas, Nicolaus, Kröger, and Wolfgang A, Bethge
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Transplantation ,Medizin ,Hematology - Published
- 2022
15. A 19-year-old patient with atypical chronic myeloid leukemia
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Thomas Ernst, Sebastian Scholl, Philipp Ernst, Thilo Koch, Hans Kreipe, Torsten Haferlach, Bernhard Theis, Björn Engmann, Ulf Schnetzke, Jochen J. Frietsch, Andreas Hochhaus, Anita Glaser, and Inken Hilgendorf
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Oncology ,medicine.medical_specialty ,Myeloid ,Hematology ,medicine.diagnostic_test ,business.industry ,General Medicine ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Internal medicine ,Biopsy ,medicine ,Atypical chronic myeloid leukemia ,Young adult ,business ,Letter to the Editor - Published
- 2020
16. Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives
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Maximilian Fleischmann, Sebastian Scholl, Andreas Hochhaus, and Ulf Schnetzke
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Gilteritinib ,Review ,Targeted therapy ,resistance ,chemistry.chemical_compound ,AML ,Internal medicine ,hemic and lymphatic diseases ,medicine ,neoplasms ,RC254-282 ,business.industry ,Venetoclax ,Myeloid leukemia ,Treatment options ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,clinical trial ,targeted therapy ,Clinical trial ,chemistry ,Flt3 mutation ,business ,Epigenetic therapy - Abstract
Simple Summary AML is a genetically heterogeneous disease with a median age of diagnosis between 60 and 70 years. Thus, many AML patients are not eligible for intensive chemotherapy. Often, the disease is accompanied by a poor prognosis due to high-risk genetic features or due to antecedent hematologic disorders (e.g., myelodysplastic syndrome). Therefore, AML treatment remains a challenge; even after intensive chemotherapy and allogeneic stem cell transplantation (alloHSCT), AML relapses are regularly observed. Thus, new concepts of AML therapy, considering tailored treatment approaches after comprehensive molecular diagnostic or implementing new immunotherapeutic strategies, are urgently needed. This review provides a detailed overview of recent developments and current promising concepts to improve the treatment and the outcome of AML patients. Abstract Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients.
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- 2021
17. Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia
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Inken Hilgendorf, Maximilian Fleischmann, Karin G. Schrenk, Florian Prims, Jochen J. Frietsch, Christian Thiede, Jakob Hammersen, Sebastian Scholl, Ulf Schnetzke, and Andreas Hochhaus
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Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Newly diagnosed ,chemistry.chemical_compound ,Refractory ,Internal medicine ,medicine ,Humans ,In patient ,Aged ,Retrospective Studies ,Sulfonamides ,business.industry ,Venetoclax ,Cytarabine ,Myeloid leukemia ,Nuclear Proteins ,General Medicine ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Myeloid, Acute ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,business - Abstract
Background Diagnosis of acute myeloid leukemia (AML) is associated with poor outcome in elderly and unfit patients. Recently, approval of the BCL-2 inhibitor venetoclax (VEN) in combination with hypo-methylating agents (HMA) led to a significant improvement of response rates and survival. Further, application in the relapsed or refractory (r/r) AML setting or in context of allogeneic stem cell transplantation (alloHSCT) seems feasible. Methods and patients Fifty-six consecutive adult AML patients on VEN from January 2019 to June 2021 were analyzed retrospectively. Patients received VEN either as first-line treatment, as subsequent therapy (r/r AML excluding prior alloHSCT), or at relapse after alloHSCT. VEN was administered orally in 28-day cycles either combined with HMA or low-dose cytarabine (LDAC). Results After a median follow-up of 11.5 (range 6.1–22.3) months, median overall survival (OS) from start of VEN treatment was 13.3 (2.2–20.5) months, 5.0 (0.8–24.3) months and 4.0 (1.5–22.1) months for first-line, subsequent line treatment and at relapse post-alloHSCT, respectively. Median OS was 11.5 (10–22.3) months from start of VEN when subsequent alloHSCT was carried out. Relapse-free survival (RFS) for the total cohort was 10.2 (2.2 – 24.3) months. Overall response rate (composite complete remission + partial remission) was 51.8% for the total cohort (61.1% for VEN first-line treatment, 52.2% for subsequent line and 42.8% at relapse post-alloHSCT). Subgroup analysis revealed a significantly reduced median OS in FLT3-ITD mutated AML with 3.4 (1.9–4.9) months versus 10.4 (0.8–24.3) months for non-mutated cases, (HR 4.45, 95% CI 0.89–22.13, p = 0.0002). Patients harboring NPM1 or IDH1/2 mutations lacking co-occurrence of FLT3-ITD showed a survival advantage over patients without those mutations (11.2 (5–24.3) months versus 5.0 (0.8–22.1) months, respectively, (HR 0.53, 95% CI 0.23 – 1.21, p = 0.131). Multivariate analysis revealed mutated NPM1 as a significant prognostic variable for achieving complete remission (CR) (HR 19.14, 95% CI 2.30 – 436.2, p Conclusion Detailed analyses on efficacy for common clinical scenarios, such as first-line treatment, subsequent therapy (r/r AML), and application prior to and post-alloHSCT, are presented. The findings suggest VEN treatment combinations efficacious not only in first-line setting but also in r/r AML. Furthermore, VEN might play a role in a subgroup of patients with failure to conventional chemotherapy as a salvage regimen aiming for potential curative alloHSCT.
- Published
- 2021
18. HHV-6 encephalitis in a non-transplanted adult acute myeloid leukemia patient
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Sebastian Scholl, Andreas Hochhaus, Margarete Voigt, Thomas Gecks, Jan Zinke, Konrad Sinn, Ulf Schnetzke, Inken Hilgendorf, and Amer Malouhi
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medicine.medical_specialty ,Hematology ,business.industry ,Oncology ,Adult Acute Myeloid Leukemia ,General Medicine ,medicine.disease ,Internal medicine ,Immunology ,Medicine ,business ,Letter to the Editor ,Encephalitis - Published
- 2021
19. A Mosquito Bite with Devastating Complications in an Immunocompromised Patient
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Florian Gras, Nils Winkelmann, Friedrich J. Hammersen, Ulf Schnetzke, Jochen J. Frietsch, T. Dönicke, Inken Hilgendorf, Andreas Hochhaus, Sebastian Scholl, Mark Lenz, and Friederike Hunstig
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0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Case Report ,Hematopoietic stem cell transplantation ,Aspergillosis ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Phlegmon ,medicine ,biology ,business.industry ,Mortality rate ,Mesh graft ,Soft tissue ,medicine.disease ,biology.organism_classification ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Surgery ,Transplantation ,Stenotrophomonas maltophilia ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Very severe aplastic anemia ,Stem cell ,business ,Aspergillus flavus - Abstract
Infectious complications such as invasive aspergillosis or infection with Stenotrophomonas maltophilia (SM) in immunocompromised patients are associated with a high mortality rate. Our report concerns a 40-year-old male newly diagnosed very severe aplastic anemia (vSAA) who in consequence of a mosquito bite was suffering from skin lesion and consecutive soft tissue phlegmon subsequent to the administration of antithymocyte globulin; a full-thickness autologous meshed skin graft successfully performed to cover skin ulcera after allogeneic stem cell transplantation (SCT). This unusual case illustrates the importance of appropriate diagnosis, anti-infective therapy and close interdisciplinary diagnostic algorithms to minimalize side effects and the selection of resistant strains and to improve patients’ outcome.
- Published
- 2019
20. Acquired thrombotic thrombocytopenic purpura after first vaccination dose of BNT162b2 mRNA COVID-19 vaccine
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Karim Kentouche, Mandy Schlosser, Gunter Wolf, Michael Baier, Ulf Schnetzke, Florian Prims, Johannes Ruhe, Andreas Hochhaus, Martin Busch, and Konstantin Herfurth
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medicine.medical_specialty ,2019-20 coronavirus outbreak ,Acquired Thrombotic Thrombocytopenic Purpura ,Hematology ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Oncology ,General Medicine ,Vaccination ,Internal medicine ,Immunology ,medicine ,business ,Letter to the Editor - Published
- 2021
21. Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments
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Maximilian Fleischmann, Sebastian Scholl, Ulf Schnetzke, and Florian H Heidel
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0301 basic medicine ,FLT3-ITD ,Antineoplastic Agents ,Review ,acute myeloid leukemia ,resistance ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,fluids and secretions ,AML ,hemic and lymphatic diseases ,FLT3-TKD ,Medicine ,Humans ,Midostaurin ,FLT3 ,lcsh:QH301-705.5 ,Protein Kinase Inhibitors ,Quizartinib ,Aniline Compounds ,business.industry ,FMS-like tyrosine kinase 3 ,Myeloid leukemia ,hemic and immune systems ,General Medicine ,Staurosporine ,crenolanib ,Transplantation ,quizartinib ,Leukemia, Myeloid, Acute ,030104 developmental biology ,midostaurin ,lcsh:Biology (General) ,chemistry ,030220 oncology & carcinogenesis ,Pyrazines ,Fms-Like Tyrosine Kinase 3 ,embryonic structures ,Cancer research ,Stem cell ,business ,gilteritinib ,Tyrosine kinase ,Crenolanib - Abstract
Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML.
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- 2020
22. Late Non-Relapse Mortality (NRM) after Standard-of-Care (SOC) CAR-T Cell Therapy for Large B-Cell Lymphoma (LBCL): Frequency, Causes, and Risk Factors.a GLA/DRST Real World Analysis
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Udo Holtick, Claudia Lengerke, Peter Borchmann, Kai Rejeski, Reinhard Marks, Claudia D. Baldus, Malte von Bonin, Bertram Glass, Francis Ayuk, Wolfgang Bethge, Christian Koenecke, Marion Subklewe, Simone Thomas, Gerald Wulf, Roland Schroers, von Tresckow Bastian, Olaf Penack, Daniel Wolff, Eva Wagner, Vladan Vucinic, Nicolaus Kröger, Dietrich W. Beelen, Maria-Luisa Schubert, Peter Dreger, Matthias Stelljes, Max S. Topp, Ulf Schnetzke, Dimitrios Mougiakakos, and Christine Hanoun
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Oncology ,medicine.medical_specialty ,Standard of care ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,Medicine ,CAR T-cell therapy ,Nonrelapse mortality ,business ,B-cell lymphoma - Abstract
Introduction Although the labeled CD19 targeting CAR-T cell constructs axi-cel and tisa-cel are generally associated with an acceptable safety profile, non-relapse deaths can occur. Little is known about timing, causes and predictors of NRM following SOC CAR-T cell therapy for LBCL. Here, we analyzed frequency, causes, and risk factors of non-relapse deaths with focus on late NRM (beyond 4 weeks after dosing) using registry data provided by the DRST, the national partner of the EBMT. Methods Patients were selected from 356 consecutive patients who received SOC CAR-T treatment of LBCL between November 2018 and April 2021 at 21 German centers and were registered with the DRST/EBMT. Baseline patient, disease, and transplant data were collected from MED-A cellular therapy forms. Centers were contacted to provide additional treatment and follow-up information. Patients with late NRM (defined as NRM occurring beyond 4 weeks after dosing without prior LBCL relapse or progression) were compared with all patients surviving progression-free the 4-week landmark after dosing without subsequent NRM. Cumulative incidences of NRM were calculated considering relapse/progression as competing event. Results The analysis set consisted of 312 patients surviving progression-free at least 28 days after CAR-T treatment and remained alive until the end of follow-up or had a documented cause of death. Median age was 61 years (19-83), 66% were male, 52% had an IPI ≥3, 13 had an ECOG score >1, 70% had received ≥3 treatment lines, 33% had failed a prior HCT, and 78% were refractory at lymphodepletion. 50% had been treated at a center contributing ≥20 cases with axi-cel (52%) or tisa-cel (48%). Grade ≥3 CRS and grade ≥3 neurotoxicity (NT) had occurred in 11% each, and 7% had no neutrophil recovery at day 100 post dosing or at last follow-up, whatever was earlier. With a median follow-up of 11.2 months, 124 patients (40%) had died, 109 (35%) LBCL-related, and 15 (5%) because of NRM. The cumulative incidence of late NRM at 12 months post dosing was 4.3% (95%CI 2.0-6.6). Causes of NRM were infections in 10 patients (bacterial or fungal sepsis/pneumonia 6; viral/atypical pneumonia/encephalitis 4); late NT 2; hyperinflammatory syndrome 1; 2 nd malignancy 1; unknown 1). Of note, 5 of the 6 lethal fungal/bacterial infections occurred subsequent to high grade NT. There was no significant difference between patients experiencing and not experiencing NRM in terms of age, gender, IPI, ECOG, pretreatment lines, prior HCT, disease status at lymphodepletion, and grade ≥3 CRS frequency. However, a significantly larger proportion of patients with late NRM had failed neutrophil recovery (27% vs 5%, p 0.011), had experienced grade ≥3 NT (40% vs 10%, p 0.0031), and/or had received axi-cel (93% vs 51%, p 0.001). Patients having neutrophil non-recovery and/or grade ≥3 NT had a 12-month NRM incidence of 16% (95%CI 5.1-26.9) vs 2.5% (95%CI 0.3-4.7) in patients with none of these 2 factors. Conclusions Late NRM in patients receiving SOC CAR-T treatment for LBCL is largely driven by infections. Risk factors for late NRM appear to be protracted neutropenia and higher grade NT, suggesting that intensified anti-bacterial/anti-fungal prophylaxis may be considered in patients with persisting critical neutropenia or exposed to high-dose steroids for NT treatment. Figure 1 Figure 1. Disclosures Dreger: BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Schubert: Gilead: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Subklewe: Miltenyi: Research Funding; Takeda: Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Klinikum der Universität München: Current Employment; MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Speakers Bureau; Janssen: Consultancy; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Bastian: Abbvie: Other; Amgen: Consultancy, Honoraria; Astra Zeneca: Honoraria, Other; BMS and Celgene: Consultancy, Honoraria, Other; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Novartis: Honoraria. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria; Merck: Consultancy; AbbVie: Other: Meeting attendance. Penack: Priothera: Consultancy; Takeda: Research Funding; Incyte: Research Funding; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria; Shionogi: Consultancy; Omeros: Consultancy. Koenecke: EUSA Pharm: Consultancy; Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. Von Bonin: Daiichi Sankyo: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Kite/Gilead: Other: traveling support and advisory fees. Stelljes: Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: MSD: Honoraria; Novartis: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring. Topp: Universitatklinikum Wurzburg: Current Employment; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Hanoun: AstraZeneca: Honoraria; Abbvie: Other: travel expenses; Novartis: Research Funding. Thomas: AbbVie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other; Kite/Gilead: Honoraria, Other, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Pfizer: Consultancy, Honoraria, Other, Speakers Bureau. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.
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- 2021
23. Gemtuzumab Ozogamicin Plus Midostaurin in Combination with Standard Intensive Induction Therapy in Newly Diagnosed AML: Results from a Phase-I Study
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Christoph Schliemann, Lars Fransecky, Martin Bornhäuser, Theresa Kretschmann, Friedrich Stoelzel, Nael Alakel, Manja Reimann, Claudia D. Baldus, Sebastian Scholl, Maher Hanoun, Knut Wendelin, Martin Wermke, Kerstin Schäfer-Eckart, Richard Noppeney, Christoph Röllig, Björn-Niklas Heydrich, Jan-Henrik Mikesch, Frank Fiebig, and Ulf Schnetzke
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Oncology ,medicine.medical_specialty ,business.industry ,Gemtuzumab ozogamicin ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,Phase i study ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Induction therapy ,medicine ,Midostaurin ,business ,medicine.drug - Abstract
Background In newly diagnosed acute myeloid leukemia (AML) with FLT3 mutations (FLT3-mut), the tyrosine kinase inhibitor midostaurin (MIDO) in combination with intensive chemotherapy (IC) is considered standard of care (SoC). Subgroup analyses from the ALFA 0701 trial indicate that the addition of the conjugated CD33 antibody gemtuzumab ozogamicin (GO) to IC increases efficacy in the FLT3-ITD subgroup of patients (pts), providing a rationale for the combined use of MIDO plus GO with IC in newly diagnosed FLT3-mut AML. On the other hand, there is evidence that the subgroup of core-binding factor (CBF) AML benefits from the inhibition of the tyrosine kinase KIT with respect to survival end points. In this respect, MIDO is a more powerful KIT inhibitor as compared to dasatinib which has been applied in previous studies. While the combination of IC plus GO in induction treatment is considered SoC in patients with CBF AML the addition of MIDO to SoC seems promising to further improve treatment outcomes in the CBF subgroup. We therefore set up the clinical trial MOSAIC composed of a phase-I part to prospectively assess the feasibility of combining MIDO plus GO with IC (MODULE), followed by a randomized phase-II part evaluating the benefit of adding GO to SoC in FLT3-mut AML (MAGMA) and of adding MIDO to SoC in CBF AML (MAGNOLIA). Here, we report the results of the phase-I part (MODULE). Methods MODULE is a dose escalation phase-I trial following a 3+3 design. Eligibility criteria include newly diagnosed AML harboring either FLT3 or CBF mutations, and fitness for IC. Standard 7+3 IC using cytarabine 200 mg/m 2 continuous infusion over 7 days plus daunorubicin 60 mg/m 2 on 3 days was combined with increasing doses of MIDO and GO in three dose levels: 1 st dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 25 mg MIDO p.o. BID days 8-21); 2 nd dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 50 mg MIDO p.o. BID days 8-21); 3 rd dose level (GO 3 mg/m 2 i.v. QD on day 1+4+7 plus 50 mg MIDO p.o. BID days 8-21). Based on the 3+3 design, each dose cohort consisted of three but maximal six pts. The protocol predefined the maximal tolerable dose (MTD) as reached if ≤2 dose-limiting toxicity events (DLTs) would occur in maximum six evaluable pts who received ≥80% of the planned study therapy. Results From September 2020 to July 2021, 11 pts were enrolled. In the 1 st dose level, three pts completed the regular study period without DLT, whereas treatment had to be discontinued in one patient on day 6 before commencement of MIDO due to infusion related reaction CTC grade 4. This patient was subsequently replaced. In the 2 nd dose level, one of three enrolled pts experienced neutropenic colitis CTC grade 3 on day 14 of treatment, which was classified as DLT. The colitis fully recovered by day 27 after commencement of treatment. As a result of the DLT, the dose cohort was subsequently extended by three additional pts. Of those, one patient developed signs of sinusoidal obstruction syndrome (SOS) CTC grade 3 starting on day 13 of treatment. SOS was classified as DLT. The patient was treated with defibrotide and supportive care until recovery on day 28. Another patient had to discontinue treatment on day 14 due to inability of swallowing MIDO. This patient was replaced as the target dose of MIDO was not reached. As predefined in the study protocol, the occurrence of 2 DLTs in six evaluable pts precluded further dose escalation to the 3 rd dose level and defined the 2 nd dose level as safe and feasible. A total number of 5 serious adverse events (SAEs) were observed among all 11 pts who completed the DLT evaluation period: infusion related reaction, colitis, parvo-B19 infection, prolonged neutropenia CTC grade 4, and SOS. An unexpected increase in frequency of common AML adverse events was not observed. The 30-day mortality among all enrolled pts was 0%. After blood count recovery, remission assessment showed complete remission (CR) in 7 pts, CR with incomplete hematologic/platelet recovery (CRi/CRp) in 3 pts and primary refractory disease in one patient. Conclusion GO standard dose on days 1 + 4 and MIDO standard dose on days 8-21 of induction treatment is defined as MTD which can be safely combined with standard IC in newly diagnosed AML. In the phase-I cohort of the MOSAIC trial, CR/CRi/CRp rates of 91% were reached. Based on the results of this dose finding trial the MTD of combined MIDO and GO will be defined as phase-II dose for the randomized phase-II studies in CBF and FLT-mut AML. Figure 1 Figure 1. Disclosures Röllig: Jazz: Honoraria; Amgen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Fransecky: Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Medac: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding.
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- 2021
24. Standard of Care CAR-T Cell Therapy for Large B-Cell Lymphoma (LBCL): Does Bridging Efficacy Matter? a German GLA/DRST Real World Analysis
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Claudia Lengerke, Peter Borchmann, Francis Ayuk, Nicolaus Kroeger, Bertram Glass, Udo Holtick, Reinhard Marks, Vladan Vucinic, Bastian von Tresckow, Olaf Penack, Matthias Stelljes, Christian Koenecke, Michael Schmitt, Marion Subklewe, Malte von Bonin, Peter Dreger, Eva-Maria Wagner-Drouet, Kai Rejeski, Max S. Topp, Ulf Schnetzke, Gerald Wulf, Roland Schroers, Dietrich W. Beelen, Wolfgang Bethge, Simone Thomas, Daniel Wolff, Dimitrios Mougiakakos, Peter Martus, and Claudia D. Baldus
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Oncology ,0303 health sciences ,medicine.medical_specialty ,Standard of care ,Bridging (networking) ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,language.human_language ,3. Good health ,German ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,language ,medicine ,CAR T-cell therapy ,business ,B-cell lymphoma ,030304 developmental biology ,030215 immunology - Abstract
Introduction The CD19 targeting CAR-T cell constructs axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have become an accepted standard salvage treatment of LBCL beyond the second line. Patients scheduled for approved CAR-T cell therapies usually have 4-8 weeks wait time for CAR-T cell infusion, thus often requiring bridging strategies in rapidly progressing patients to achieve disease control until start of lymphodepletion. It is still unclear, however, if the adverse impact of active progressive lymphoma can be overcome by successful bridging. We have addressed this question using registry data provided by the German Registry for Stem Cell Transplantation (DRST), the national partner of the EBMT. Methods We analyzed 356 consecutive patients who received standard of care axi-cel (n=173) or tisa-cel (n=183) treatment of LBCL between November 2018 and April 2021 at 21 German centers and were registered with the DRST/EBMT. Baseline patient, disease, and transplant data were collected from MED-A cellular therapy forms. Centers were contacted to provide additional treatment and follow-up information. Predictors of progression-free survival (PFS) were analyzed by uni- and multivariate comparisons. Results Compared to the approval trials, patients were of poor risk with 58% presenting with elevated LDH at lymphodepletion and 71% having received ≥3 pretreatment lines, resulting in ineligibility for the ZUMA-1 study in 87% of cases. Kaplan-Maier estimates of overall survival, PFS and non-relapse mortality (NRM) 12 months after dosing were 52%, 30% and 7%, respectively. Information on bridging was available for 355 patients (99%). Of these, 279 patients (78%) underwent at least one line of bridging attempt, whereas bridging was deemed unnecessary in 76 patients (22%). A wide variety of modalities were employed for bridging, with the most frequent being chemoimmunotherapy (n=188), chemotherapy (n=41), radiation (n=30), immunotherapy (n=12) and steroids (n=6). Bridging resulted in disease control (CR/PR) in 58 of 270 patients evaluable for response (21%). With a median follow-up of 11 months, 12-month PFS rates for patients without bridging, successful bridging, and bridging failure were 41%, 52%, and 20%, respectively, p= Conclusion The results of this large German GLA/DRST analysis suggest that effective bridging can overcome the adverse impact of active disease on the outcome of standard-of-case CD19 CAR-T therapy. With current treatment strategies, however, bridging is often unsuccessful, highlighting the need for exploring innovative tools for inducing temporary LBCL control for CAR-T therapy preparation. Figure 1 Figure 1. Disclosures Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Schmitt: TolerogenixX: Current holder of individual stocks in a privately-held company; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Other: Travel grants; Hexal: Other: Travel grants, Research Funding. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Borchmann: Gilead Sciences: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria. Subklewe: Klinikum der Universität München: Current Employment; Pfizer: Consultancy, Speakers Bureau; Roche: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MorphoSys: Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Takeda: Speakers Bureau; Miltenyi: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. von Tresckow: Roche: Consultancy, Honoraria; Kite-Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pentixafarm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Kroeger: Novartis: Honoraria; AOP Pharma: Honoraria; Gilead/Kite: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Wulf: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Marks: Merck: Consultancy; Kite/Gilead: Honoraria; AbbVie: Other: Meeting attendance; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Penack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; Omeros: Consultancy; Shionogi: Consultancy; Priothera: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Therakos: Honoraria; Pfizer: Honoraria; Neovii: Honoraria; Novartis: Honoraria; MSD: Honoraria. Koenecke: Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; EUSA Pharm: Consultancy. Von Bonin: Kite/Gilead: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Daiichi Sankyo: Other: traveling support and advisory fees. Stelljes: Amgen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Topp: Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Universitatklinikum Wurzburg: Current Employment. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Thomas: Abbvie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel support; Kite-Gilead: Honoraria, Other: travel support, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Dreger: Bluebird Bio: Consultancy; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; AstraZeneca: Consultancy, Speakers Bureau.
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- 2021
25. Aggressives B-Zell-Lymphom: Registerstudien bestätigen die Wirksamkeit von CAR-T-Zell-Therapien
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Ulf Schnetzke
- Abstract
Seit 3 Jahren sind in Europa die beiden CAR-T-Zell-Produkte Tisagenlecleucel (Tisa-Cel) und Axicabtagene Ciloleucel (Axi-Cel) für das aggressive diffus-großzellige B-Zell-Lymphom (DLBCL) und das transformierte follikuläre Lymphom (trFL) beim Erwachsenen nach mindestens 2 vorangegangenen systemischen Therapielinien zugelassen. Axi-Cel ist außerdem zugelassen für die Behandlung des primären mediastinalen B-Zell-Lymphom [1, 2]. Seit Dezember 2020 ist ein drittes CAR-T-Produkt, Brexucabtagen Autoleucel (Brexu-Cel) für die Behandlung des vorbehandelten Mantelzelllymphoms zugelassen worden [3]. Alle 3 genannten Studien, welche zur Zulassung der entsprechenden Produkte geführt haben, waren Phase-2-Studien mit den bekannten Limitationen, wobei hier vor allem die geringe Patientenzahl zu nennen ist. Aus diesem Grund kommt Registerdaten aus den für diese Therapie spezialisierten Zentren eine besondere Bedeutung zu. Diese Analysen an einem großen Patientenkollektiv zeigen nicht nur das Therapieansprechen, sondern vor allem potenzielle Nebenwirkungen, auch im Langzeitverlauf, auf. Insbesondere das Zytokin-Freisetzungssyndrom (CRS) und die Neurotoxizität (ICANS) wurden im Vorfeld und während der Einführung der CAR-T-Zell-Produkte viel diskutiert [4]. Sesques und Kollegen konnten 2020 eine erste große Analyse eines französischen Zentrums publizieren, für welche 61 Patienten untersucht wurden, die entweder Tisa-Cel oder Axi-Cel erhielten. Eine Bridging-Therapie bekamen nahezu alle Patienten (97%), wobei diese zu 98% eine Kombination aus Fludarabin und Cyclophosphamid war. Das mediane Alter der Patienten zum Zeitpunkt der CAR-T-Infusion lag bei 59 Jahren, der Großteil hatte ein DLBCL (62%) bzw. ein transformiertes follikuläres Lymphom (29%). Die meisten Patienten (70%) hatten bereits 4 oder mehr Vortherapien vor der Leukapherese erhalten, wobei eine Hochdosis-Chemotherapie mit autologer Blutstammzelltransplantation bei 28% durchgeführt wurde. Zwischen den beiden Produkten, Tisa-Cel und Axi-Cel gab es keine signifikanten Unterschiede hinsichtlich der Patientencharakteristika. Bezüglich der Ansprechraten ist vor allem der Monat 3 nach Therapie von Bedeutung, da inzwischen bekannt ist, dass ein komplettes Therapieansprechen (CR) zu diesem Zeitpunkt als sehr günstig zu bewerten ist. Es zeigte sich zum Monat 3 ein Gesamtansprechen (ORR) von 45% und eine CR-Rate von 39%. Bei einer kurzen medianen Nachbeobachtungszeit von 5,7 Monaten betrug das mediane progressionsfreie Überleben (PFS) 3 Monate und das mediane Gesamtüberleben (OS) 11,8 Monate. Das PFS nach 6 Monaten betrug 44%. Risikofaktoren, welche in der multivariaten Analyse mit einem schlechteren Therapieansprechen assoziiert waren, sind eine erhöhte Laktatdehydrogenase (LDH), die Anzahl an Vortherapien und ein erhöhtes C-reaktives Protein (CRP). Hinsichtlich der im Vorfeld viel diskutierten Nebenwirkungen trat ein CRS bei 85% der Patienten auf, Grad 3 oder höher bei 8%, ein ICANS bei 28%, Grad 3 oder höher bei 10%. An Langzeitnebenwirkung sind vordergründig die Zytopenien (Anämie, Thrombopenie und Neutropenie) zu nennen, welche auch 30 Tage nach Infusion und darüber hinaus von klinischer Relevanz sind. Keine Unterschiede bestanden in Wirksamkeit und Sicherheit zwischen den beiden Produkten.
- Published
- 2021
26. Isoform localization of Dectin-1 regulates the signaling quality of anti-fungal immunity
- Author
-
Michael Fischer, Oliver Kurzai, Andreas Hochhaus, Ulf Schnetzke, Bärbel Spies-Weisshart, Christine Gräfe, Sebastian Scholl, Kerstin Hünniger, and Jörg P. Müller
- Subjects
0301 basic medicine ,Gene isoform ,medicine.diagnostic_test ,medicine.medical_treatment ,Immunology ,Cell ,Biology ,Flow cytometry ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cytokine ,medicine.anatomical_structure ,Cell culture ,medicine ,Immunology and Allergy ,Cytokine secretion ,Signal transduction ,Cellular localization ,030215 immunology - Abstract
Dectin-1 is recognized as a major receptor for fungal s-glucans and contributes to anti-fungal immunity. Human monocyte populations express Dectin-1 isoforms A and B, which differ by the presence of a stalk region and its N-linked glycosylation site. Here, we analyzed the expression of both isoforms in human monocyte-derived cells. The cellular localization on cell lines stably expressing either Dectin-1 isoform A or B was studied by flow cytometry and confocal laser scanning microscopy. Intracellular protein signaling and cytokine production were analyzed by immunoblotting and cytometric bead array, respectively. Monocyte-derived cells showed cell type-specific expression of the two isoforms. Glycosylated Dectin-1 isoform A was predominantly localized at the cell surface, non-glycosylated isoform B was retained intracellularly. Inhibition of glycosylation resulted in efficient abrogation of cell surface expression of isoform A. Signaling quality following Dectin-1 stimulation was reduced in isoform B cells. Differential isoform specific cytokine secretion was observed by cytometric bead array. We show here that n-glycosylation of Dectin-1 is crucial for its cell surface expression and consequently signal transduction. Taken together, unique cytokine secretion and varying expression levels of human Dectin-1 isoforms on monocyte-derived cells may indicate distinct isoform usage as a cell type-specific mechanism of regulating anti-fungal immunity.
- Published
- 2017
27. The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML
- Author
-
Sebastian Scholl, Yordan Sbirkov, Anne Kresinsky, Melanie Kahl, Thomas Ernst, Tino Schenk, Florian H. Heidel, Kevin Petrie, Frank Böhmer, Annamaria Brioli, Giorgia Simonetti, Martin Bens, Arthur Zelent, Marco Groth, Giovanni Martinelli, Florian Perner, Ulf Schnetzke, Anna Hinze, Andreas Hochhaus, and Sven Stengel
- Subjects
0301 basic medicine ,Acute promyelocytic leukemia ,Cancer Research ,Myeloid ,Cellular differentiation ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Differentiation therapy ,hemic and lymphatic diseases ,medicine ,neoplasms ,sub_healthsciences ,Myeloid leukemia ,Hematology ,medicine.disease ,Leukemia ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Acetyltransferase ,Cancer research ,biology.protein ,Demethylase ,sub_biomedicalsciences - Abstract
To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.
- Published
- 2019
28. The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML
- Author
-
Melanie, Kahl, Annamaria, Brioli, Martin, Bens, Florian, Perner, Anne, Kresinsky, Ulf, Schnetzke, Anna, Hinze, Yordan, Sbirkov, Sven, Stengel, Giorgia, Simonetti, Giovanni, Martinelli, Kevin, Petrie, Arthur, Zelent, Frank-Dietmar, Böhmer, Marco, Groth, Thomas, Ernst, Florian H, Heidel, Sebastian, Scholl, Andreas, Hochhaus, and Tino, Schenk
- Subjects
Histone Demethylases ,Genotype ,Cell Membrane ,Apoptosis ,Cell Differentiation ,HL-60 Cells ,Tretinoin ,Epigenesis, Genetic ,Histones ,Leukemia, Myeloid, Acute ,HEK293 Cells ,Leukemia, Promyelocytic, Acute ,Bone Marrow ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Leukocytes, Mononuclear ,Humans ,p300-CBP Transcription Factors - Abstract
To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.
- Published
- 2019
29. Correction: The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML
- Author
-
Thomas Ernst, Frank-Dietmar Böhmer, Tino Schenk, Kevin Petrie, Anne Kresinsky, Annamaria Brioli, Melanie Kahl, Yordan Sbirkov, Sven Stengel, Anna Hinze, Florian Perner, Florian H. Heidel, Ulf Schnetzke, Giorgia Simonetti, Sebastian Scholl, Marco Groth, Giovanni Martinelli, Martin Bens, Arthur Zelent, and Andreas Hochhaus
- Subjects
Cancer Research ,Oncology ,business.industry ,Acetyltransferase ,Cancer research ,Medicine ,Hematology ,business - Published
- 2020
30. Polymorphisms of Toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia
- Author
-
M von Lilienfeld-Toal, Tobias Rachow, Bärbel Spies-Weisshart, Karin G. Schrenk, Sebastian Scholl, Andreas Hochhaus, Olaposi Yomade, Anita Glaser, Michael Fischer, and Ulf Schnetzke
- Subjects
medicine.medical_specialty ,Myeloid ,Immunology ,Biology ,Polymorphism, Single Nucleotide ,Sepsis ,Internal medicine ,Genetics ,medicine ,Genetic predisposition ,Humans ,Genetics (clinical) ,Retrospective Studies ,Myeloid leukemia ,Induction chemotherapy ,Retrospective cohort study ,Pneumonia ,Odds ratio ,medicine.disease ,Toll-Like Receptor 2 ,Toll-Like Receptor 4 ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure - Abstract
Infectious complications continue to be one of the major causes of morbidity and mortality in patients with acute myeloid leukemia (AML). Several single-nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) can affect the genetic susceptibility to infections or even sepsis. We sought to investigate the impact of different SNPs on the incidence of developing sepsis and pneumonia in patients with newly diagnosed AML following induction chemotherapy. We analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) gene in a cohort of 155 patients with AML who received induction chemotherapy. The risk of developing sepsis and pneumonia was assessed by multiple logistic regression analyses. The presence of the TLR2 Arg753Gln polymorphism was significantly associated with pneumonia in AML patients (odds ratio (OR): 10.78; 95% confidence interval (CI): 2.0-58.23; P=0.006). Furthermore, the cosegregating TLR4 polymorphisms Asp299Gly and Thr399Ile were independent risk factors for the development of both sepsis and pneumonia (OR: 3.55; 95% CI: 1.21-10.4, P=0.021 and OR: 3.57, 95% CI: 1.3-9.86, P=0.014, respectively). To our best knowledge, this study represents the first analysis demonstrating that polymorphisms of TLR2 and TLR4 influence the risk of infectious complications in patients with AML undergoing induction chemotherapy.
- Published
- 2014
31. Functional acute liver failure after treatment with pegylated asparaginase in a patient with acute lymphoblastic leukemia: potential impact of plasmapheresis
- Author
-
Ulf Schnetzke, Sebastian Scholl, Andreas Hochhaus, and Wibke Göpel
- Subjects
medicine.medical_specialty ,Potential impact ,Hematology ,business.industry ,medicine.medical_treatment ,Lymphoblastic Leukemia ,Induction chemotherapy ,General Medicine ,medicine.disease ,Gastroenterology ,Portal vein thrombosis ,03 medical and health sciences ,0302 clinical medicine ,Cholestasis ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,030211 gastroenterology & hepatology ,Plasmapheresis ,business ,Intensive care medicine ,After treatment - Published
- 2016
32. Efficacy and feasibility of cyclophosphamide combined with intermediate- dose or high-dose cytarabine for relapsed and refractory acute myeloid leukemia (AML)
- Author
-
Paul La Rosée, Sebastian Scholl, Karin G. Schrenk, Peter Fix, Baerbel Spies-Weisshart, Hans-Joerg Fricke, Ulf Schnetzke, Andreas Hochhaus, and Anita Glaser
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Cyclophosphamide ,DNA Mutational Analysis ,Salvage therapy ,Young Adult ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,neoplasms ,Aged ,Retrospective Studies ,Salvage Therapy ,business.industry ,Cytarabine ,Induction chemotherapy ,Myeloid leukemia ,General Medicine ,Middle Aged ,medicine.disease ,Survival Analysis ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,Drug Resistance, Neoplasm ,Feasibility Studies ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Approximately, 70 % of adult patients with de novo acute myeloid leukemia (AML) achieve a complete remission (CR) while 10-20 % of AML are refractory to induction chemotherapy. Furthermore, a significant proportion of AML patients in CR will relapse during or after consolidation treatment. There is no evidence for a standard salvage regimen and most centers use a combination of an anthracycline and cytarabine (AraC). The aim of this study was to investigate the impact of two age-adjusted regimens containing AraC and cyclophosphamide applied for the treatment of relapsed or refractory AML.We retrospectively analyzed 60 patients (24 male, 36 female; median age 56 years) with relapsed or refractory AML who were treated with a combination of AraC and cyclophosphamide monocentrically between October 2000 and January 2013. Two different protocols containing either high-dose (hAC) or intermediate-dose cytarabin (iAC) have been applied dependent on age and performance status.We demonstrate an overall response rate (CR + PR) induced by hAC and iAC of 56.7 %. Importantly, a complete remission rate (CR + CRp) of 52.2 % was found in patients who received the hAC regimen while only 8.8 % of patients achieved a CR following the iAC protocol (p0.001). The rate of refractory disease was 26.1 and 47.1 %, respectively. High-risk cytogenetics, i.e., a complex aberrant or monosomal karyotype had no effect on achievement of CR after hAC. In addition, there was no impact of activating FLT3 mutations on response to treatment according to the hAC regimen. In the cohort of patients treated with the iAC protocol, treatment-related mortality of 11.8 % within 60 days was observed but none of the patients who received the hAC regimen died within the first 2 months following chemotherapy. The toxicity profile was acceptable at both cytarabine dose levels. Importantly, 19 patients (82.6 %) of the hAC cohort underwent allogeneic hematopoietic stem cell transplantation (HSCT) as consecutive treatment.The hAC regimen represents a promising therapeutic approach to induce a second CR in younger patients with relapsed or refractory AML prior to HSCT without using anthracyclines.
- Published
- 2014
33. Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia
- Author
-
Michael Fischer, Ulf Schnetzke, Bärbel Spies-Weisshart, Andreas Hochhaus, Maximilian Fleischmann, Mario Walther, Sebastian Scholl, and Inken Hilgendorf
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Amino Acid Motifs ,Gene Expression ,03 medical and health sciences ,fluids and secretions ,0302 clinical medicine ,Protein Domains ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Idarubicin ,Humans ,Online Only Articles ,Survival analysis ,Retrospective Studies ,Mitoxantrone ,Base Sequence ,business.industry ,Cytarabine ,Myeloid leukemia ,Induction chemotherapy ,Genetic Variation ,hemic and immune systems ,Retrospective cohort study ,Hematology ,Induction Chemotherapy ,Sequence Analysis, DNA ,Survival Analysis ,Leukemia, Myeloid, Acute ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,Tandem Repeat Sequences ,030220 oncology & carcinogenesis ,embryonic structures ,Fms-Like Tyrosine Kinase 3 ,Immunology ,business ,medicine.drug - Abstract
FLT3 mutations represent the most frequent molecular aberrations in acute myeloid leukemia (AML), and are associated with a higher probability of relapse and worse outcome. Activating mutations of FLT3 predominantly comprise internal tandem duplications (FLT3-ITDs), and can be detected in up to 30%
- Published
- 2016
34. Isoform localization of Dectin-1 regulates the signaling quality of anti-fungal immunity
- Author
-
Mike, Fischer, Jörg P, Müller, Bärbel, Spies-Weisshart, Christine, Gräfe, Oliver, Kurzai, Kerstin, Hünniger, Andreas, Hochhaus, Sebastian, Scholl, and Ulf, Schnetzke
- Subjects
Glycosylation ,Microscopy, Confocal ,Macrophages ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Flow Cytometry ,Monocytes ,Cell Line ,Mycoses ,Cytokines ,Humans ,Protein Isoforms ,Lectins, C-Type ,Signal Transduction - Abstract
Dectin-1 is recognized as a major receptor for fungal ß-glucans and contributes to anti-fungal immunity. Human monocyte populations express Dectin-1 isoforms A and B, which differ by the presence of a stalk region and its N-linked glycosylation site. Here, we analyzed the expression of both isoforms in human monocyte-derived cells. The cellular localization on cell lines stably expressing either Dectin-1 isoform A or B was studied by flow cytometry and confocal laser scanning microscopy. Intracellular protein signaling and cytokine production were analyzed by immunoblotting and cytometric bead array, respectively. Monocyte-derived cells showed cell type-specific expression of the two isoforms. Glycosylated Dectin-1 isoform A was predominantly localized at the cell surface, non-glycosylated isoform B was retained intracellularly. Inhibition of glycosylation resulted in efficient abrogation of cell surface expression of isoform A. Signaling quality following Dectin-1 stimulation was reduced in isoform B cells. Differential isoform specific cytokine secretion was observed by cytometric bead array. We show here that n-glycosylation of Dectin-1 is crucial for its cell surface expression and consequently signal transduction. Taken together, unique cytokine secretion and varying expression levels of human Dectin-1 isoforms on monocyte-derived cells may indicate distinct isoform usage as a cell type-specific mechanism of regulating anti-fungal immunity.
- Published
- 2016
35. The E3 ubiquitin ligase TRAF2 can contribute to TNF-α resistance in FLT3-ITD-positive AML cells
- Author
-
Bärbel Spies-Weisshart, Ulf Schnetzke, Elisabeth Zirm, Andreas Hochhaus, Jörg P. Müller, Sebastian Scholl, and Michael Fischer
- Subjects
Cancer Research ,TRAF2 ,Blotting, Western ,Apoptosis ,Real-Time Polymerase Chain Reaction ,Glycogen Synthase Kinase 3 ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Humans ,RNA, Messenger ,Phosphorylation ,RNA, Small Interfering ,Protein kinase B ,Cell Proliferation ,Glycogen Synthase Kinase 3 beta ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Necrosis Factor-alpha ,NF-kappa B ,Hematology ,TNF Receptor-Associated Factor 2 ,Ubiquitin ligase ,Leukemia, Myeloid, Acute ,fms-Like Tyrosine Kinase 3 ,Oncology ,Drug Resistance, Neoplasm ,Tandem Repeat Sequences ,biology.protein ,Cancer research ,Tumor necrosis factor alpha ,Signal transduction ,FLT3 Inhibitor ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
TNF-α has pleiotropic effects on cell survival and apoptosis. The E3 ubiquitin ligase TRAF2 plays a crucial role for TNF-α mediated signaling since NF-κB activation by TNF-α is at least partially mediated by TRAF2. The objective of this study was to investigate whether TNF-α can induce apoptosis in FLT3-ITD-positive AML cells and to elucidate the influence of TRAF2. Stable lentiviral mediated down-regulation of TRAF2 resulted in a decrease of phosphorylation of the anti-apoptotic protein AKT and its downstream target GSK-3β. Induction of apoptosis and impaired proliferation after TNF-α exposure were observed. Co-treatment of FLT3-ITD-positive cells with the specific FLT3 inhibitor AC220 was able to overcome TNF-α resistance. Taken together, we conclude that TRAF2 plays an important role in signal transduction and survival of AML cells.
- Published
- 2013
36. Treosulfan, Fludarabine and Cytarabine As Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation
- Author
-
Jochen J. Frietsch, Andreas Hochhaus, Jochen Casper, Ulf Schnetzke, Inken Hilgendorf, Sebastian Scholl, Friederike Hunstig, and Nils Winkelmann
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Treosulfan ,medicine.disease ,Biochemistry ,Fludarabine ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Graft-versus-host disease ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cytarabine ,Bone marrow ,Myelofibrosis ,business ,030215 immunology ,medicine.drug - Abstract
Background: The combination of treosulfan witth fludarabine was successfully introduced into toxicity-reduced conditioning regimens for hematopoietic stem cell transplantation (HCT). However, the risk of post-HCT relapse remains of concern. Here we report for the first time on the results of an individual treatment approach with treosulfan, fludarabin and cytarabine as conditioning for allogeneic HCT in patients with AML, MPN or MDS. Methods: 22 patients were treated with fludarabine 30 mg/m² given on day -6 to day -2, treosulfan 14 g/m² administered on days -4 to day -2 and cytarabin 2g/m² given on days -6 and -5. GvHD-prophylaxis consisted of cyclosporine A and methotrexate or MMF. In addition, antithymocyte globulin was applied in case of an unrelated donor. One patient received bone marrow and the remaining patients received peripheral blood stem cells from matched related donors (9%), matched unrelated donors (73%) or mismatched unrelated donors (18%). All patients were considered to have high risk of relapse because of unfavourable cytogenetic features and/or insufficient or missing response to previous treatment. Three patients (14 %) with CML after blast crisis received the combination because of the reported high relapse rate (46%) after three-day scheduled conditioning with treosulfan [1]. In addition, patients were considered to be ineligible for myeloablative standard conditioning because of multi-morbidity (n = 4; 18% with HCT-CI >2) and/or age >55 years (n = 14; 64%). Results: The median age of patients was 59 (35-68) years. Patients suffered from acute myeloid leukemia (n = 14, 64%), myeloproliferative neoplasia (n = 6, 27%) or myelodysplasic syndrome (n = 2, 9%). The conditioning regime was well tolerated and nearly all patients engrafted and achieved complete donor-type chimerism, except for one who died very early from sepsis. Another patient with underlying myelofibrosis suffered from secondary graft failure on day 100. Two patients developed aGVHD °III/ IV. None of the patients suffered from veno-occlusive disease or severe chronic GVHD. Overall survival and event-free survival at one year reached 60.2% and 59.6%, respectively. Six patients died from infectious disease, two from relapse and one patient from acute GVHD °IV. Conclusion: The combination of cytarabine with the established conditioning of treosulfan and fludarabine is feasible in patients with high risk of relapse and ineligible for myeloablative standard conditioning. Holowiecki J, Giebel S, Wojnar J et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic 334 haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 335 2008; 142(2): 284-92. Disclosures Hilgendorf: Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Frietsch:Deutsche Krebshilfe: Research Funding. Scholl:Abbivie: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support. Hochhaus:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Casper:Medac: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding.
- Published
- 2018
37. Paradoxical MAPK-activation in response to treatment with tyrosine kinase inhibitors in CML: Flow cytometry loses track
- Author
-
Michael B. Fischer, Andreas Hochhaus, J. H. Clement, Paul La Rosée, Andreas Finkensieper, Ulf Schnetzke, and Jochen J. Frietsch
- Subjects
MAPK/ERK pathway ,Histology ,medicine.diagnostic_test ,Kinase ,Cell ,Cell Biology ,Biology ,Molecular biology ,Pathology and Forensic Medicine ,Flow cytometry ,medicine.anatomical_structure ,Western blot ,Cell culture ,medicine ,Cytometry ,Tyrosine kinase - Abstract
Background Paradoxical activation of the MAP-kinases, ERK1, and ERK2 (ERK1/2) is observed in CML cell lines and primary CML patient cells treated with tyrosine kinase inhibitors (TKI) in vitro. The commonly accepted assumption is that activated ERK1/2 is key regulators of survival of leukemic cells treated with kinase inhibitors. Hence, paradoxical ERK1/2-activation may trigger resistance in vivo, which yet has to be shown. We therefore sought to establish a flow cytometric assay that enables us to measure paradoxical TKI-induced ERK1/2-activation on a single cell basis in primary CML cells. Methods Side-by-side Western blot and intracellular flow cytometry (FCM) after in vitro exposure of cell lines and primary cells to nilotinib were performed. Detailed analysis of pre-analytical factors and the issue of compartmentalization of phosphorylated ERK1/2 by confocal laser scanning microscopy were performed. Result Results were conflicting in that pERK-activation was robustly detected in Western blot assays, but not when cells were analyzed by FCM despite well functioning positive and negative controls. This is in contrast to experiments on other targets such as phospho-CrkL, where also in our hands TKI-dependent inhibition of phosphorylation is trackable by both Western blot and FCM assays. Conclusions To our knowledge this is the first report of discordant results in phospho-protein analysis in TKI-treated cells analyzed by Western blot vs. FCM. We speculate that a substance specific interaction interferes with fluorescence dependent methods seeking to track phosphorylated ERK1/2 in TKI-treated cells. © 2013 International Clinical Cytometry Society.
- Published
- 2013
38. Impact of NOD2 polymorphisms on infectious complications following chemotherapy in patients with acute myeloid leukaemia
- Author
-
Sebastian Scholl, Olaposi Yomade, Andreas Hochhaus, Anita Glaser, Ulf Schnetzke, and Bärbel Spies-Weisshart
- Subjects
Adult ,Male ,Neutropenia ,Myeloid ,Mutation, Missense ,Nod2 Signaling Adaptor Protein ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Sepsis ,Immunocompromised Host ,Young Adult ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Mucositis ,Humans ,Genetic Predisposition to Disease ,Frameshift Mutation ,Aged ,Aged, 80 and over ,Induction chemotherapy ,Bacterial Infections ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Immunity, Innate ,digestive system diseases ,Neoplasm Proteins ,Systemic inflammatory response syndrome ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Mycoses ,Immunology ,Female - Abstract
We sought to investigate the relationship between polymorphisms of the NOD2 gene and infectious complications following intensive induction chemotherapy in patients with acute myeloid leukaemia (AML). We hypothesised that single nucleotide polymorphisms (SNPs) of the NOD2 gene are associated with a higher rate of infections during the phase of severe neutropenia. In 131 AML patients receiving induction therapy, the presence of the three most frequent polymorphisms of NOD2 (Arg702Trp, Gly908Arg, Leu1007fsinsC) was analysed. SNP analyses by means of genomic PCR incorporating fluorescence-labelled probes with characteristic melting curves were performed using the LightCycler platform. Our data suggest a significantly lower probability of mucositis or enteritis in AML patients lacking any of the three evaluated NOD2 polymorphisms. Furthermore, bloodstream cultures of AML patients carrying either a missense or a frameshift mutation of NOD2 were significantly more frequently tested positive concerning Streptococcus spp. In contrast, the presence of NOD2 polymorphisms had no impact on such important infectious complications as systemic inflammatory response syndrome or sepsis, the rate of central venous catheter infections or the incidence of pneumonia including fungal infections. Our data represent one of the first reports investigating the impact of polymorphisms of the innate immune system on infectious complications in patients with neutropenia following chemotherapy. A correlation between NOD2 polymorphisms and infectious events in AML patients is demonstrated.
- Published
- 2013
39. Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment
- Author
-
Andreas Hochhaus, Sebastian Scholl, Herbert G. Sayer, Volker Schmidt, Ulf Schnetzke, Karin G. Schrenk, Inken Hilgendorf, and Maximilian Fleischmann
- Subjects
Oncology ,Male ,Cancer Research ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Gene Duplication ,Ponatinib ,Imidazoles ,Myeloid leukemia ,General Medicine ,Induction Chemotherapy ,Middle Aged ,Sorafenib ,Prognosis ,Pyridazines ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,Adult ,Niacinamide ,medicine.medical_specialty ,Allogeneic transplantation ,Antineoplastic Agents ,Disease-Free Survival ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,CD135 ,Humans ,Transplantation, Homologous ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,business.industry ,Phenylurea Compounds ,Induction chemotherapy ,Transplantation ,chemistry ,fms-Like Tyrosine Kinase 3 ,Fms-Like Tyrosine Kinase 3 ,Cancer research ,business ,030215 immunology ,Stem Cell Transplantation - Abstract
Activating mutations of the receptor tyrosine kinase FLT3 (fms-related tyrosine kinase 3) reflect the most frequent molecular aberration in acute myeloid leukemia (AML). In particular, FLT3 internal tandem duplications (FLT3-ITD) are characterized by an unfavorable prognosis and allogeneic stem cell transplantation (allogeneic SCT) in first complete remission is recommended. In case of imminent or frank relapse following allogeneic SCT, treatment with FLT3 tyrosine kinase inhibitors (TKI) constitutes a promising clinical approach to induce hematologic remission without conventional chemotherapy. We retrospectively analyzed the response to induction chemotherapy and the outcome of 76 patients with FLT3-ITD-positive AML including 50 patients who underwent allogeneic SCT. Furthermore, efficacy of TKI treatment was evaluated in 18 patients (median age 54 years, range 21–74) with relapsed or refractory FLT3-ITD-positive AML. Response to induction chemotherapy in 76 FLT3-ITD-positive AML patients was characterized by a complete remission (CR) rate of 68%. In total, 50 of 76 patients (66%) underwent allogeneic SCT including 40 patients (80%) in CR. Relapse of AML was observed in 21 of 47 patients (45%) after allogeneic SCT with a median relapse-free survival (RFS) of 13 months (range 3–224) for patients with CR prior to or at day +30 after SCT. Myeloablative conditioning resulted in an improved median RFS of 29 months (4–217) as compared to a reduced intensity conditioning protocol prior to allogeneic SCT with a RFS of 8 months (1–197, P = 0.048), respectively. Median OS of FLT3-ITD-positive AML was 17 months (5–225) for patients who received an allogeneic SCT as compared to 9 months (1–184) for patients who did not undergo SCT. Response of FLT3-ITD-positive AML to sorafenib was characterized by only 3 of 18 patients achieving a bone marrow response (17%), while there was no response to second-line treatment with ponatinib. This “real-life” data reflect the continuing challenge of FLT3-ITD-positive AML and confirm the poor outcome even after allogeneic SCT. Furthermore, efficacy of TKI treatment of relapsed or refractory FLT3-ITD AML is still limited and requires substantial improvement, e.g., by the introduction of second-generation inhibitors targeting constitutively active FLT3.
- Published
- 2016
40. Polymorphisms of Dectin-1 and TLR2 Predispose to Invasive Fungal Disease in Patients with Acute Myeloid Leukemia
- Author
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Bernd Gruhn, Karin G. Schrenk, Susan Wittig, Ulf Schnetzke, Sebastian Scholl, Michael Fischer, Andreas Hochhaus, Anita Glaser, and Baerbel Spies-Weisshart
- Subjects
Male ,0301 basic medicine ,Heredity ,Myeloid ,Pulmonology ,Cancer Treatment ,Gene Expression ,lcsh:Medicine ,Pathology and Laboratory Medicine ,Monocytes ,Hematologic Cancers and Related Disorders ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Antineoplastic Combined Chemotherapy Protocols ,Medicine and Health Sciences ,lcsh:Science ,Fungal Pathogens ,Multidisciplinary ,Pharmaceutics ,Gene Expression Regulation, Leukemic ,Fungal Diseases ,Fungal genetics ,Pattern recognition receptor ,Myeloid leukemia ,Hematology ,Middle Aged ,Myeloid Leukemia ,Neoplasm Proteins ,Genetic Mapping ,Leukemia, Myeloid, Acute ,Leukemia ,Infectious Diseases ,medicine.anatomical_structure ,Oncology ,Medical Microbiology ,030220 oncology & carcinogenesis ,Cancer Therapy ,Female ,Cellular Types ,Pathogens ,Research Article ,Acute Myeloid Leukemia ,Adult ,Immune Cells ,Immunology ,Variant Genotypes ,Single-nucleotide polymorphism ,Mycology ,Biology ,Microbiology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Drug Therapy ,Leukemias ,Genetics ,medicine ,Chemotherapy ,Humans ,Genetic Predisposition to Disease ,Lectins, C-Type ,Microbial Pathogens ,Aged ,Blood Cells ,Lung Diseases, Fungal ,lcsh:R ,Cancers and Neoplasms ,Biology and Life Sciences ,Induction chemotherapy ,Pneumonia ,Cell Biology ,medicine.disease ,Toll-Like Receptor 2 ,TLR2 ,030104 developmental biology ,lcsh:Q - Abstract
Background Patients with acute myeloid leukemia (AML) who undergo induction chemotherapy are at high risk for invasive fungal disease (IFD). Dectin-1, a C-type lectin family member represents one of the most important pattern recognition receptors of the innate immune system and single nucleotide polymorphisms (SNPs) in the Dectin-1 gene have been associated with an increased risk of infectious complications. We sought to investigate the impact of three different Dectin-1 SNPs and one TLR2 SNP on developing IFD in 186 adult patients with newly diagnosed AML following anthracycline-based induction chemotherapy. Patients and methods Genotyping of Dectin-1 SNPs (rs16910526, rs3901533 and rs7309123) and TLR2 SNP (rs5743708) was performed by TaqMan method and pyrosequencing. IFD was defined according to the EORTC/MSG consensus guidelines. Multiple logistic regression analyses were applied to evaluate the association between the polymorphisms and the occurrence of pulmonary infections. Dectin-1 expression studies with SNP genotyped human monocytes were performed to elucidate susceptibility to IFD following chemotherapy. Results We could demonstrate that patients carrying the Dectin-1 SNP rs7309123 G/G (n = 47) or G/G and C/G (n = 133) genotype revealed a significant higher risk for developing both pneumonia in general (adjusted odds ratio (OR): 2.5; p = 0.014 and OR: 3.0, p = 0.004) and pulmonary IFD (OR: 2.6; p = 0.012 and OR: 2.4, p = 0.041, respectively). Patients carrying the TLR2 SNP rs5743708 (R753Q, GA/AA genotype, n = 12) also revealed a significantly higher susceptibility to pneumonia including IFD. Furthermore, Dectin-1 mRNA expression in human monocytes was lower following chemotherapy. Conclusion To our best knowledge, this study represents the first analysis demonstrating that harbouring polymorphisms of Dectin-1 (rs7309123) or TLR2 (rs5743708) represents an independent risk factor of developing IFD in patients with AML undergoing induction chemotherapy.
- Published
- 2016
41. Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ
- Author
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Sebastian Scholl, Reinhard Bauer, Deepika Arora, Sabine Stopp, Rinesh Godfrey, Ulf Schnetzke, Jörg P. Müller, Sylvia-Annette Böhmer, Theresa Heinrich, Arne Östman, Markus Dagnell, and Frank-D. Böhmer
- Subjects
Immunology ,Cell ,Phosphatase ,Protein tyrosine phosphatase ,Biology ,Transfection ,complex mixtures ,Biochemistry ,Mice ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,Mice, Inbred C3H ,Receptor-Like Protein Tyrosine Phosphatases, Class 3 ,HEK 293 cells ,Myeloid leukemia ,Cell Biology ,Hematology ,respiratory system ,Oxidants ,respiratory tract diseases ,Cell biology ,Leukemia, Myeloid, Acute ,Cell Transformation, Neoplastic ,HEK293 Cells ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,Tandem Repeat Sequences ,Cell culture ,embryonic structures ,Signal transduction ,Reactive Oxygen Species ,Oxidation-Reduction - Abstract
Signal transduction of FMS-like tyrosine kinase 3 (FLT3) is regulated by protein-tyrosine phosphatases (PTPs). We recently identified the PTP DEP-1/CD148/PTPRJ as a novel negative regulator of FLT3. This study addressed the role of DEP-1 for regulation of the acute myeloid leukemia (AML)–related mutant FLT3 internal tandem duplication (ITD) protein. Our experiments revealed that DEP-1 was expressed but dysfunctional in cells transformed by FLT3 ITD. This was caused by enzymatic inactivation of DEP-1 through oxidation of the DEP-1 catalytic cysteine. In intact cells, including primary AML cells, FLT3 ITD kinase inhibition reactivated DEP-1. DEP-1 reactivation was also achieved by counteracting the high levels of reactive oxygen species (ROS) production detected in FLT3 ITD–expressing cell lines by inhibition of reduced NAD phosphate (NADPH)–oxidases, or by overexpression of catalase or peroxiredoxin-1 (Prx-1). Interference with ROS production in 32D cells inhibited cell transformation by FLT3 ITD in a DEP-1–dependent manner, because RNAi-mediated depletion of DEP-1 partially abrogated the inhibitory effect of ROS quenching. Reactivation of DEP-1 by stable overexpression of Prx-1 extended survival of mice in the 32D cell/C3H/HeJ mouse model of FLT3 ITD–driven myeloproliferative disease. The study thus uncovered DEP-1 oxidation as a novel event contributing to cell transformation by FLT3 ITD.
- Published
- 2012
42. Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors
- Author
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Nicolai Härtel, Thomas Schenk, Philipp Erben, P La Rosée, Ulf Schnetzke, A. Hochhaus, Juliana Schwaab, and Thomas Klag
- Subjects
Harringtonines ,Cancer Research ,Blotting, Western ,Fusion Proteins, bcr-abl ,Apoptosis ,Pharmacology ,Biology ,Real-Time Polymerase Chain Reaction ,Piperazines ,Mice ,chemistry.chemical_compound ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Omacetaxine mepesuccinate ,medicine ,Animals ,RNA, Messenger ,Receptors, Cytokine ,Progenitor cell ,Protein Kinase Inhibitors ,Cells, Cultured ,Cell Proliferation ,Precursor Cells, B-Lymphoid ,Imatinib ,Hematology ,Protein-Tyrosine Kinases ,Antineoplastic Agents, Phytogenic ,Pyrimidines ,Imatinib mesylate ,Oncology ,chemistry ,Nilotinib ,Drug Resistance, Neoplasm ,Homoharringtonine ,Benzamides ,Imatinib Mesylate ,Neoplastic Stem Cells ,Stem cell ,Tyrosine kinase ,medicine.drug - Abstract
Overcoming resistance against BCR-ABL-inhibitors in chronic myeloid leukemia (CML) is central to prevent progression to advanced phase disease. Kinase mutations of BCR-ABL and cytokine-mediated modulation of response to tyrosine kinase inhibitors (TKIs) are key mechanisms governing clinical response to imatinib and second generation TKIs. Omacetaxine mepesuccinate is effective in imatinib-resistant CML with reported stem cell activity. We specifically thought to explore omacetaxine in the context of the pan-resistant mutant T315I, and in its potential to modify cytokine-dependent resistance. Omacetaxine was investigated in cell lines and primary CD34+ enriched progenitor cells from patients with CML. Addition of cytokines, shown to revert the efficacy of TKIs in BCR-ABL-positive cells, does not affect omacetaxine mediated antiproliferative activity, neither in cell lines nor in primary CML CD34+ progenitor cells. Looking at potential mechanisms, we found marked downregulation of the common β-subunit c of the cytokine-receptors (cCRβc) for IL3, IL5 and GM-CSF by omacetaxine in cell lines and primary progenitor cultures. The observed cytokine-independent in-vitro cytotoxicity of omacetaxine may be explained by downregulation of cCRβc. Whether this can be used clinically as a means to optimize the stem cell activity of TKIs merits further evaluation.
- Published
- 2012
43. Detection of Enterococcus spp. in bronchoalveolar lavage fluid of patients with high-risk neutropenia: May it be ignored?
- Author
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Ulf Schnetzke, Andreas Hochhaus, Max Desole, Sebastian Scholl, and Karin G. Schrenk
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,medicine.drug_class ,Secondary infection ,Antibiotics ,Gastroenterology ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Neoplasm Staging ,Aged, 80 and over ,medicine.diagnostic_test ,biology ,business.industry ,General Medicine ,Bacterial Infections ,biochemical phenomena, metabolism, and nutrition ,Middle Aged ,medicine.disease ,biology.organism_classification ,Prognosis ,Hematologic Diseases ,Pneumonia ,030104 developmental biology ,Bronchoalveolar lavage ,Oncology ,Enterococcus ,Vancomycin ,Female ,business ,Bronchoalveolar Lavage Fluid ,Febrile neutropenia ,medicine.drug ,Follow-Up Studies - Abstract
We present a series of eight patients with hematological diseases predominantly including AML patients with longlasting neutropenia (Table 1). All patients are characterized by febrile neutropenia, the development of pulmonary infiltrates and comprehensive diagnostic evaluation including bronchoscopy. In all patients, Enterococcus spp. were isolated from bronchoalveolar lavage (BAL), while the majority of these samples contained at least 10,000 bacteria per ml of BAL fluid. Importantly, four out of five Enterococcus strains were characterized by resistance to vancomycin. Thus, half of all BAL specimens were tested positive concerning vancomycin-resistant enterococci (VRE). The consideration of additional BAL findings and the clinical course lead to the assumption that secondary infection with Enterococcus spp. represents the most frequent mechanism how Enterococci can contribute to pneumonia in these immunocompromised patients. In addition, primary infection with E. faecalis was supposed in one of the eight investigated patients. Nevertheless, potential effects of additional antibiotics used in these patients, e.g., empiric antifungal treatment, need to be discussed. Only a few reports on pulmonary infections that are caused by Enterococcus spp. have been published. In detail, in two large analyses of serious enterococcal infections only 4–5 % of patients had pleuropulmonary infections (Garrison et al. 1982; Patterson et al. 1995). This stands remarkably in contrast to our single-center observation of eight cases of nosocomial respiratory enterococcal infections during the last 2 years. We do not query the origin of pulmonary enterococci from resident oropharyngeal flora. In contrast, the relationship between resident Enterococcus spp. and their isolation from BAL has to be reconsidered, especially in such analyses demonstrating a high concentration of bacteria or indicating a potentially relevant resistance profile, e.g., VRE. Dear editor
- Published
- 2015
44. Different clones of acute leukemia after successful treatment of Hodgkin’s disease
- Author
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Sebastian Scholl, Bärbel Spies-Weisshart, Ulf Schnetzke, Andreas Hochhaus, Karin G. Schrenk, and Christa Kunert
- Subjects
Oncology ,medicine.medical_specialty ,Acute leukemia ,Hodgkin s ,Hematology ,business.industry ,General Medicine ,Disease ,Minimal residual disease ,Text mining ,Internal medicine ,Flt3 mutation ,medicine ,business ,Leukemic Blasts - Published
- 2014
45. Efficacy of antifungal prophylaxis with oral suspension posaconazole during induction chemotherapy of acute myeloid leukemia
- Author
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Karin G. Schrenk, Marie von Lilienfeld-Toal, Sebastian Scholl, Ulf Schnetzke, Katy Stegemann, and Andreas Hochhaus
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Posaconazole ,Myeloid ,Antifungal Agents ,Administration, Oral ,law.invention ,Cohort Studies ,Young Adult ,Randomized controlled trial ,Suspensions ,law ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Randomized Controlled Trials as Topic ,Retrospective Studies ,Hematology ,business.industry ,Myeloid leukemia ,Induction chemotherapy ,Retrospective cohort study ,General Medicine ,Induction Chemotherapy ,Middle Aged ,Triazoles ,medicine.disease ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Mycoses ,Immunology ,Female ,business ,medicine.drug - Abstract
Severe infectious complications reflect a continuing problem in patients with acute myeloid leukemia (AML). Based on data from a randomized clinical trial demonstrating a reduction of proven and probable invasive fungal disease (IFD), posaconazole has been approved for prophylaxis of fungal infections in AML patients during induction chemotherapy. Nevertheless, recently published observational studies show contradictory results concerning the efficacy of posaconazole in this clinical setting. Furthermore, oral suspension posaconazole is associated with an unpredictable bioavailability that especially depends on nutritional factors or gastric pH value.We retrospectively analyzed the impact of posaconazole prophylaxis in 70 consecutively evaluable AML patients who underwent induction chemotherapy at a tertiary care hospital. The incidence of IFD classified as proven, probable or possible, antifungal therapy including empiric treatment in high-risk patients and tolerability of posaconazole were determined. In addition, important clinical cofactors such as co-treatment with proton pump inhibitors and risk factors for pneumonia were analyzed in this study.We can demonstrate that posaconazole is well tolerated and had to be stopped in only six patients (8.6%). The overall incidence of IFD was 30% including two patients with proven (2.8%), four patients with probable (5.7%) and 15 patients with possible IFD (21.4%). Importantly, 24 out of 49 patients (49.0%) who did not fulfill the criteria of IFD received empiric antifungal therapy. Including patients classified as possible IFD, 39 of 70 patients (55.7%) underwent at least first-line antifungal treatment.Our "real-life" data obtained from 70 AML patients after induction chemotherapy demonstrate the frequent necessity of systemic antifungal treatment despite prophylaxis with oral suspension posaconazole.
- Published
- 2015
46. Leriche’s syndrome and Löffler endocarditis in a 30-year-old patient presenting with hypereosinophilic syndrome
- Author
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Andreas Reiter, Thomas Klag, Ulf Schnetzke, Paul La Rosée, Jürgen Zanow, Sebastian Scholl, Rudolf Benz, Andreas Hochhaus, Anita Glaser, and Tudor C. Pörner
- Subjects
Abdominal pain ,medicine.medical_specialty ,medicine.diagnostic_test ,Hypereosinophilic syndrome ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Gastroenterology ,medicine.anatomical_structure ,Internal medicine ,Eosinophilic ,medicine ,Prednisolone ,Endocarditis ,Eosinophilia ,Bone marrow ,medicine.symptom ,business ,medicine.drug ,Fluorescence in situ hybridization - Abstract
Dear Editor, Here, we report a severe complication of hypereosinophilic syndrome (HES), the onset of Leriche’s syndrome, in a 30year-old patient. A 30-year-old man was referred to our institution due to acute onset of severe pain and symmetric sensory neuropathy of both legs. Contrast enhanced computed tomography showed occlusion of aortic bifurcation (Leriche’s syndrome) (Fig. 1a). Immediate thrombectomy secured reperfusion of the lower limbs. Histopathologic workup confirmed the presence of thrombotic material. Three weeks prior to admission, the patient had been diagnosed with a hypereosinophilic syndrome and Loffler’s endocarditis. At that time, he had presented with nonspecific abdominal pain accompanied by diarrhea and progressive general weakness that he had observed for more than 2 months. Diagnostic workup showed an abnormal eosinophil count 7.5 (10/l) with a corresponding myeloproliferative bone marrow. Fluorescence in situ hybridization (FISH) analysis for rearrangements of the platelet-derived growth factor receptors alpha and beta (PDGFRα/β) were evaluated as negative (LSI 4q12 Tri-Color Rearrangement probe set; Poseidon Repeat Free, 5q33, Break probe). Echocardiography indicated the presence of Loffler endocarditis. Intracardial thrombotic formations had been detectable. Oral anticoagulation with phenprocoumone had been started, and an INR between 2 and 3 was targeted. When Leriche’s syndrome was diagnosed, the INR was 2.0. The patient had been treated with prednisolone (1 g) for 2 days with a temporary drop of eosinophilis to 1.8 (10/l). At admission, hematologic workup confirmed massive increase of eosinophils 3.6 (10/l). Screening for causes of reactive eosinophilia was negative with regard to an allergic reaction and autoimmune, parasitic, or helminthic diseases. Echocardiography confirmed Loffler’s endocarditis (Fig. 1b). Examination of the bone marrow showed a hypercellular marrow with marked increase of eosinophilic granulocytes and their progenitors (Fig. 1c). Standard cytogenetic characterization showed a normal karyotype. Using the FIP1L1Chic2-PDGFRα dual-color probe which is optimized to detect the Chic2 deletion at 4q12 FISH analysis found a deletion in chromosome 4, band q12 [del(4)(q12)] (Fig. 1d). Thomas Klag and Thomas Schnetzke have contributed equally to this work.
- Published
- 2011
47. Drug-induced lymphadenopathy with eosinophilia and renal failure mimicking lymphoma disease: dramatic onset of DRESS syndrome associated with antibiotic treatment
- Author
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Andreas Hochhaus, Martin Freesmeyer, Ulf Schnetzke, Theo Bossert, Paul La Rosée, and Sebastian Scholl
- Subjects
medicine.medical_specialty ,Creatinine ,medicine.drug_class ,business.industry ,Antibiotics ,Hematology ,General Medicine ,medicine.disease ,Gastroenterology ,Surgery ,chemistry.chemical_compound ,Tubular proteinuria ,chemistry ,Internal medicine ,medicine ,Ceftriaxone ,Eosinophilia ,Endocarditis ,Vancomycin ,medicine.symptom ,business ,Cefuroxime ,medicine.drug - Abstract
Dear Editor,Here, we report a rare complication of antibiotic treatmentleading to lymphoma-mimicking lymphadenopathy withconcomitant eosinophilia, dermatitis, and acute renalfailure.A 30-year-old man was admitted for aortic valvereplacement because of endocarditis. The medical historyrevealed insulin-dependent diabetes mellitus (type 1),diabetic retinopathy, vascular disease, hypertension, andstage 2 chronic renal failure. Five weeks prior to admission,transesophageal echocardiography had revealed acuteinfectious endocarditis of the aortic valve and moderateaortic valve insufficiency. Blood cultures were positive forStreptococcus dysgalactiae and antibiotic therapy withpenicillin G and gentamycin was initiated. Penicillin Gwas replaced by vancomycin due to exanthema; gentamy-cin was stopped. Control echocardiography showed severevalve insufficiency, which prompted surgical valve replace-ment. Antibiotic treatment with vancomycin was continuouslyadministered.Ten days after successful surgery, the patient developedacute renal failure (creatinine, 637 μmol/l; reference range(rr), 74–110 μmol/l) requiring single-time hemodialysis.Concomitantly, the patient developed fever with a dailyintermittent pattern (max., 39.7°C) and an elevated whiteblood cell count (35.1/nl; rr, 4.4–11.3/nl) showing a leftshift in the differential count. C-reactive protein wassignificantly elevated (189 mg/ml). Antibiotic therapy withvancomycin, gentamycin, and ceftriaxone did not result inany improvement. The antibiotic therapy was changed tolinezolid/tigecycline; later, to rifampicin, cefuroxime, andfluconazole, without improving symptoms. Echocardiogra-phy showed no signs of acute infectious endocarditis. Bloodcultures were negative. Peripheral lymphadenopathy promp-ted further imaging studies, including a FDG–PET–CT scanwhich showed ubiquitous, highly metabolic, active lymph-adenopathy ranging between 7 and 25 mm in size (Fig. 1a).When the hematology consultant was called in fordiagnosis of suspected lymphoma, the leukocytes hadincreased to 40/nl, and the differential revealed 24%eosinophils. IgE levels were significantly elevated(42,684 kU/l; rr
- Published
- 2011
48. Paradoxical MAPK-activation in response to treatment with tyrosine kinase inhibitors in CML: flow cytometry loses track
- Author
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Ulf, Schnetzke, Mike, Fischer, Jochen J, Frietsch, Andreas, Finkensieper, Joachim H, Clement, Andreas, Hochhaus, and Paul, La Rosée
- Subjects
Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Antigens, CD34 ,Flow Cytometry ,Enzyme Activation ,Mice ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Neoplastic Stem Cells ,Tumor Cells, Cultured ,Animals ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Line, Transformed - Abstract
Paradoxical activation of the MAP-kinases, ERK1, and ERK2 (ERK1/2) is observed in CML cell lines and primary CML patient cells treated with tyrosine kinase inhibitors (TKI) in vitro. The commonly accepted assumption is that activated ERK1/2 is key regulators of survival of leukemic cells treated with kinase inhibitors. Hence, paradoxical ERK1/2-activation may trigger resistance in vivo, which yet has to be shown. We therefore sought to establish a flow cytometric assay that enables us to measure paradoxical TKI-induced ERK1/2-activation on a single cell basis in primary CML cells.Side-by-side Western blot and intracellular flow cytometry (FCM) after in vitro exposure of cell lines and primary cells to nilotinib were performed. Detailed analysis of pre-analytical factors and the issue of compartmentalization of phosphorylated ERK1/2 by confocal laser scanning microscopy were performed.Results were conflicting in that pERK-activation was robustly detected in Western blot assays, but not when cells were analyzed by FCM despite well functioning positive and negative controls. This is in contrast to experiments on other targets such as phospho-CrkL, where also in our hands TKI-dependent inhibition of phosphorylation is trackable by both Western blot and FCM assays.To our knowledge this is the first report of discordant results in phospho-protein analysis in TKI-treated cells analyzed by Western blot vs. FCM. We speculate that a substance specific interaction interferes with fluorescence dependent methods seeking to track phosphorylated ERK1/2 in TKI-treated cells.
- Published
- 2013
49. The E3 ubiquitin ligase TRAF6 inhibits LPS-induced AKT activation in FLT3-ITD-positive MV4-11 AML cells
- Author
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M. Fischer, Andreas Hochhaus, Bärbel Spies-Weisshart, Jörg P. Müller, Ulf Schnetzke, Sebastian Scholl, Elisabeth Zirm, and Anne-Kathrin Kuhn
- Subjects
Lipopolysaccharides ,Cancer Research ,Ubiquitin-Protein Ligases ,Blotting, Western ,Apoptosis ,Real-Time Polymerase Chain Reaction ,Phosphatidylinositol 3-Kinases ,Tumor Cells, Cultured ,Humans ,RNA, Messenger ,Phosphorylation ,RNA, Small Interfering ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,TNF Receptor-Associated Factor 6 ,Gene knockdown ,biology ,Chemistry ,Reverse Transcriptase Polymerase Chain Reaction ,NF-kappa B ,General Medicine ,Flow Cytometry ,Ubiquitin ligase ,Toll-Like Receptor 4 ,IκBα ,Leukemia, Myeloid, Acute ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,fms-Like Tyrosine Kinase 3 ,biology.protein ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Tumor necrosis factor alpha ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The aim of the study was to investigate the activation of the PI3K/AKT (phosphatidylinositol-3-kinase) pathway after stimulation of TLR-4 (Toll-like receptor 4) with LPS (lipopolysaccharide) in FLT3-ITD (internal tandem duplication)-positive AML (acute myeloid leukemia) cells. TRAF6 (tumor necrosis factor receptor-associated factor 6), an E3 ubiquitin ligase, is critically involved in TLR-signaling. Based on the observation that TRAF6 might play a role in AKT phosphorylation, we hypothesized that TRAF6 can enhance the constitutive FLT3-ITD-driven activation of AKT after LPS stimulation. Human MV4-11 FLT3-ITD cells were silenced for TRAF6 by stable shRNA expression. Western blotting was used to analyze signal transduction by detection of phosphorylated proteins. LPS-induced activation of the NF-κB pathway was ensured by the induction of IκBα expression. To evaluate a potential functional role of TRAF6, we also performed chemosensitivity assays. In MV4-11 cells, AKT was activated in response to LPS treatment. Surprisingly, shRNA-mediated knockdown of TRAF6 resulted in a significant increase in basal AKT phosphorylation. By LPS stimulation, the gain of AKT phosphorylation was more pronounced in the TRAF6 knockdown cell line than in the control. In addition, the concentration-dependent induction of apoptosis in response to treatment with the cytostatic drugs cytarabine or daunorubicin was significantly reduced in TRAF6-depleted MV4-11 cells. Our data strongly suggest that the E3 ubiquitin ligase TRAF6 plays an important functional role in signal transduction and survival of AML cells. We hypothesize that LPS-mediated stimulation of TLR-4 leads to the induction of NF-κB-mediated signaling. However, TRAF6 might prevent a synergistic activation of the PI3K/AKT pathway after activation of TLR-4 signaling in FLT3-ITD-positive cells.
- Published
- 2012
50. Hypothermic injury: the mitochondrial calcium, ATP and ROS love-hate triangle out of balance
- Author
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Ralf Lösel, Martin Wehling, Fokko J. van der Woude, P.-T. Brinkkoetter, Grietje Beck, Yuxi Feng, Benito A. Yard, Uwe Gottmann, Ulf Schnetzke, Hui Song, Christine Hanusch, and Peter Schnuelle
- Subjects
medicine.medical_specialty ,Programmed cell death ,Physiology ,Dopamine ,Intracellular Space ,chemistry.chemical_element ,Mitochondrion ,Calcium ,Biology ,Models, Biological ,Electron Transport ,Adenosine Triphosphate ,Internal medicine ,Tissue damage ,medicine ,Humans ,Cells, Cultured ,Calcium metabolism ,Cell Death ,Ionomycin ,Hypothermia ,Mitochondria ,Endothelial stem cell ,Cold Temperature ,Endocrinology ,Biochemistry ,chemistry ,Catecholamine ,medicine.symptom ,Reactive Oxygen Species ,Oxidation-Reduction ,medicine.drug - Abstract
Catecholamines prevent hypothermic cell death which accounts for severe tissue damage and impaired allograft function after prolonged organ preservation. Here, we identified cellular processes which govern hypothermia-mediated cell death in endothelial cells and how they are influenced by dopamine.Lactate dehydrogenase assay, intracellular ATP, reactive oxygen species and reduced thio-group measurement, intracellular calcium measurement and mitochondrial calcium staining were performed in the study.Intracellular ATP was almost completely depleted within 12 hrs of hypothermic preservation in untreated human umbilical vein endothelial cells (HUVEC), while dopamine pre-treatment significantly delayed ATP depletion. 4 hrs after hypothermia a redox imbalance was observed in untreated cells, which increased with the duration of hypothermia. The redox imbalance was primarily caused by depletion of SH reduction equivalents and was significantly inhibited by dopamine. In addition, hypothermia-induced Ca(2+) influx and mitochondrial Ca(2+) accumulation were both prevented by dopamine. The protective effect of dopamine was abrogated by ionomycin and sodium azide and partly by oligomycin and CCCP.Our data demonstrated that loss of intracellular ATP, generation of a redox imbalance and accumulation of intracellular Ca(2+) underlie cold preservation injury. Dopamine improves the redox balance, prevents intracellular Ca(2+) accumulation and delays ATP depletion.
- Published
- 2008
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