Publications by authors named "Michael Koldehoff"

46 Publications

2021 update of the AGIHO guideline on evidence-based management of COVID-19 in patients with cancer regarding diagnostics, viral shedding, vaccination and therapy.

Eur J Cancer 2021 Feb 10;147:154-160. Epub 2021 Feb 10.

Department of Haematology and Medical Oncology, Clinic for Internal Medicine II, University Hospital Jena, Jena, Germany; Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.

The worldwide spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated infectious coronavirus disease (COVID-19) has posed a unique challenge to medical staff, patients and their families. Patients with cancer, particularly those with haematologic malignancies, have been identified to be at high risk to develop severe COVID-19. Since publication of our previous guideline on evidence-based management of COVID-19 in patients with cancer, research efforts have continued and new relevant data has come to light, maybe most importantly in the field of vaccination studies. Therefore, an update of our guideline on several clinically important topics is warranted. Here, we provide a concise update of evidence-based recommendations for rapid diagnostics, viral shedding, vaccination and therapy of COVID-19 in patients with cancer. This guideline update was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology by critically reviewing the currently available data on these topics applying evidence-based medicine criteria.
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http://dx.doi.org/10.1016/j.ejca.2021.01.033DOI Listing
February 2021

Evaluation of Three Commercial PCR Assays for the Detection of Azole-Resistant from Respiratory Samples of Immunocompromised Patients.

J Fungi (Basel) 2021 Feb 11;7(2). Epub 2021 Feb 11.

Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

This is the first study comparing three commercially available PCR assays for the detection of DNA from respiratory specimen of immunocompromised patients and the presence of gene mutations. Bronchoalveolar lavages (BALs, = 103) from patients with haematological/oncological underlying diseases were retrospectively investigated. The performance of three PCR assays, namely MycoGENIE Real-Time PCR Kit (Adamtech), Fungiplex Azole-R IVD Real-Time PCR Kit (Bruker Daltonik GmbH) and AsperGenius (PathoNostics B.V.), were evaluated. All patients were categorised following current EORTC/MSG criteria, with exclusion of the PCR-results. From the 11 invasive pulmonary aspergillosis (IPA) probable samples, eight were detected with MycoGENIE, resulting in a sensitivity of 80% and a specificity of 73%. Furthermore, Fungiplex resulted in six positive BALs with a sensitivity of 60% and a specificity of 91% and AsperGenius in seven positive BAL samples, with a sensitivity of 64% and a specificity of 97%. No proven IPA was detected. One isolate showed phenotypically an azole-resistance, which was also detected in each of the tested PCR assays with the mutation in TR34. The here tested PCR assays were capable of reliably detecting DNA, as well as differentiation of the common gene mutations. However, evaluation on the AsperGenius assay revealed a low risk of false positive results.
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http://dx.doi.org/10.3390/jof7020132DOI Listing
February 2021

Cytomegalovirus kinetics after hematopoietic cell transplantation reveal peak titers with differential impact on mortality, relapse and immune reconstitution.

Am J Hematol 2021 Jan 13. Epub 2021 Jan 13.

Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany.

Even in the era of PCR-based monitoring, prophylaxis, and preemptive therapy, Cytomegalovirus (CMV) viremia remains a relevant cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, studies using binary analysis (presence/absence of CMV) reported contradicting data for NRM, overall survival and leukemia relapse. Here, we analyzed CMV replication kinetics in 11 508 whole blood PCR samples of 705 patients with HCT between 2012 and 2017. Using two independent models based on CMV peak titers and on the time point of first CMV reactivation, we stratified patients into risk cohorts. Each cohort had distinct cellular immune reconstitution profiles and differentiated for relevant clinical outcomes. Patients with high CMV peak titers had significantly reduced overall survival (HR 2.13, 95% CI 1.53-2.96; p < .0001), due to high NRM. Early impaired T cell reconstitution was a risk factor for high CMV peak titers, however relevant CMV viremia also related to boosted T cell reconstitution. Importantly, intermediate CMV peak titers associated with a significantly reduced relapse probability (HR 0.53, 95% CI 0.31-0.91; p = .022). In short, CMV kinetics models distinguished relevant clinical outcome cohorts beyond the R+ serostatus with distinct immune reconstitution patterns and resolve in part contradicting results of previous studies exclusively focused on the presence or absence of CMV.
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http://dx.doi.org/10.1002/ajh.26094DOI Listing
January 2021

Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

Ann Hematol 2020 Nov 16. Epub 2020 Nov 16.

Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1-19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRD, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
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http://dx.doi.org/10.1007/s00277-020-04321-xDOI Listing
November 2020

Evidence-based management of COVID-19 in cancer patients: Guideline by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Eur J Cancer 2020 11 21;140:86-104. Epub 2020 Sep 21.

Department of Haematology and Medical Oncology, Clinic for Internal Medicine II, University Hospital Jena, Jena, Germany; Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.

Since its first detection in China in late 2019 the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated infectious disease COVID-19 continue to have a major impact on global healthcare and clinical practice. Cancer patients, in particular those with haematological malignancies, seem to be at an increased risk for a severe course of infection. Deliberations to avoid or defer potentially immunosuppressive therapies in these patients need to be balanced against the overarching goal of providing optimal antineoplastic treatment. This poses a unique challenge to treating physicians. This guideline provides evidence-based recommendations regarding prevention, diagnostics and treatment of SARS-CoV-2 infection and COVID-19 as well as strategies towards safe antineoplastic care during the COVID-19 pandemic. It was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) by critically reviewing the currently available data on SARS-CoV-2 and COVID-19 in cancer patients applying evidence-based medicine criteria.
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http://dx.doi.org/10.1016/j.ejca.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505554PMC
November 2020

Long-Term Survival Benefit after Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia.

Biol Blood Marrow Transplant 2020 Oct 9. Epub 2020 Oct 9.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.007DOI Listing
October 2020

Central venous catheter-related infections in hematology and oncology: 2020 updated guidelines on diagnosis, management, and prevention by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).

Ann Hematol 2021 Jan 30;100(1):239-259. Epub 2020 Sep 30.

Department of Hematology and Oncology, Red Cross Hospital Munich, Munich, Germany.

Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter-related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients.
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http://dx.doi.org/10.1007/s00277-020-04286-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782365PMC
January 2021

Veno-Venous Extracorporeal Membrane Oxygenation in Adult Patients with Sickle Cell Disease and Acute Chest Syndrome: a Single-Center Experience.

Hemoglobin 2020 Mar 14;44(2):71-77. Epub 2020 Apr 14.

Department of Bone Marrow Transplantation, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, Essen, Germany.

Acute chest syndrome (ACS) in adult patients with sickle cell disease represents a leading cause of death. It is characterized by a new density on chest X-ray accompanied by fever and/or respiratory symptoms. Currently, 49 adult patients with sickle cell disease are registered at our department. By now, 12 patients (24.5%) suffered from ACS and two patients showed multiple/recurrent (>2) episodes. Death in one patient was related to acute respiratory failure secondary to ACS. In three patients with ACS, invasive mechanical ventilation and subsequent veno-venous extracorporeal membrane oxygenation (VV-ECMO) was mandatory. Veno-venous ECMO was applied within 24 hours upon arrival to the intensive care unit (ICU). All patients were treated aggressively for ACS including exchange transfusions [packed red blood cell (pRBC) units 5-16] maintaining a Hb S threshold of <30.0% in addition to broad-spectrum antibiotics, resulting in a successful outcome following decannulation from VV-ECMO (49 hours, 251 hours, 30 min., and 98 hours, respectively). Limited information is presently available on the use of VV-ECMO in adult patients with sickle cell disease in the context of acute respiratory failure secondary to ACS. The adequate timing of the decision to place ECMO in critically ill adults with sickle cell disease, incapable of being treated by conventional mechanical ventilation secondary to very severe vaso-occlusive crisis (VOC), might further reduce mortality rates while treating the underlying condition.
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http://dx.doi.org/10.1080/03630269.2020.1745827DOI Listing
March 2020

Treatment of invasive fungal diseases in cancer patients-Revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

Mycoses 2020 Jul 12;63(7):653-682. Epub 2020 May 12.

Division of Haematology & Oncology, Department of Internal Medicine, Charité University Medicine, Campus Benjamin Franklin, Berlin, Germany.

Background: Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient's risk factors (eg length and depth of granulocytopenia) and the expected side effects.

Objectives: Since the last edition of recommendations for 'Treatment of invasive fungal infections in cancer patients' of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possible invasive fungal diseases (IFDs) towards pre-emptive therapy of probable IFD.

Methods: The guideline was prepared by German clinical experts for infections in cancer patients in a stepwise consensus process. MEDLINE was systematically searched for English-language publications from January 1975 up to September 2019 using the key terms such as 'invasive fungal infection' and/or 'invasive fungal disease' and at least one of the following: antifungal agents, cancer, haematological malignancy, antifungal therapy, neutropenia, granulocytopenia, mycoses, aspergillosis, candidosis and mucormycosis.

Results: AFT of IFDs in cancer patients may include not only antifungal agents but also non-pharmacologic treatment. In addition, the armamentarium of antifungals for treatment of IFDs has been broadened (eg licensing of isavuconazole). Additional antifungals are currently under investigation or in clinical trials.

Conclusions: Here, updated recommendations for the treatment of proven or probable IFDs are given. All recommendations including the levels of evidence are summarised in tables to give the reader rapid access to key information.
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http://dx.doi.org/10.1111/myc.13082DOI Listing
July 2020

Baseline Chest Computed Tomography as Standard of Care in High-Risk Hematology Patients.

J Fungi (Basel) 2020 Mar 13;6(1). Epub 2020 Mar 13.

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Excellence Center for Medical Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.

Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. The estimated numbers of annually treated hematology patients, chest imaging timepoints and techniques, IPA rates, and follow-up imaging were assessed. In total, 142 physicians from 43 countries participated. The specialties included infectious diseases ( = 69; 49%), hematology ( = 68; 48%), and others ( = 41; 29%). BCT was performed in 57% ( = 54) of 92 hospitals. Upon the diagnosis of malignancy or admission, 48% and 24% performed BCT, respectively, and X-ray was performed in 48% and 69%, respectively. BCT was more often used in hematopoietic cell transplantation and in relapsed acute leukemia. European centers performed BCT in 59% and non-European centers in 53%. Median estimated IPA rate was 8% and did not differ between BCT (9%; IQR 5-15%) and non-BCT centers (7%; IQR 5-10%) (p = 0.69). Follow-up computed tomography (CT) for IPA was performed in 98% ( = 90) of centers. In high-risk hematology patients, baseline CT is becoming a standard-of-care. Chest X-ray, while inferior, is still widely used. Randomized, controlled trials are needed to investigate the impact of BCT on patient outcome.
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http://dx.doi.org/10.3390/jof6010036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151030PMC
March 2020

Optimizing anti-T-lymphocyte globulin dosing to improve long-term outcome after unrelated hematopoietic cell transplantation for hematologic malignancies.

Am J Transplant 2020 03 16;20(3):677-688. Epub 2019 Nov 16.

Department of Bone Marrow Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany.

Prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT) remains challenging. Because prospective randomized trials of in-vivo T cell depletion using anti-T-lymphocyte globulin (ATLG) in addition to a calcineurin inhibitor and methotrexate (MTX) led to conflicting outcome results, we evaluated the impact of ATLG on clinical outcome, lymphocyte- and immune reconstitution survival models. In total, 1500 consecutive patients with hematologic malignancies received matched unrelated donor (MUD) HCT with cyclosporin and MTX (N = 723, 48%) or with additional ATLG (N = 777, 52%). In the ATLG cohort, grades III-IV acute (12% vs 23%) and extensive chronic GVHD (18% vs 34%) incidences were significantly reduced (P < .0001). Nonrelapse mortality (27% vs 45%) and relapse (30% vs 22%) differed also significantly. Event-free and overall survival estimates at 10 years were 44% and 51% with ATLG and 33% and 35% without ATLG (P < .002 and <.0001). A dose-dependent ATLG effect on lymphocyte- and neutrophil reconstitution was observed. At ATLG exposure, lymphocyte counts and survival associated through a logarithmically increasing function. In this survival model, the lymphocyte count optimum range at exposure was between 0.4 and 1.45/nL (P = .001). This study supports additional ATLG immune prophylaxis and is the first study to associate optimal lymphocyte counts with survival after MUD-HCT.
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http://dx.doi.org/10.1111/ajt.15642DOI Listing
March 2020

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation.

J Clin Oncol 2019 02 7;37(5):375-385. Epub 2018 Nov 7.

1 Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT).

Methods: We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS).

Results: A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434).

Conclusion: Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.
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http://dx.doi.org/10.1200/JCO.2018.79.2184DOI Listing
February 2019

Cytomegalovirus induces HLA-class-II-restricted alloreactivity in an acute myeloid leukemia cell line.

PLoS One 2018 29;13(1):e0191482. Epub 2018 Jan 29.

Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital of Essen, Essen, Germany.

Cytomegalovirus (HCMV) reactivation is found frequently after allogeneic hematopoietic stem cell transplantation (alloSCT) and is associated with an increased treatment-related mortality. Recent reports suggest a link between HCMV and a reduced risk of cancer progression in patients with acute leukemia or lymphoma after alloSCT. Here we show that HCMV can inhibit the proliferation of the acute myeloid leukemia cell line Kasumi-1 and the promyeloid leukemia cell line NB4. HCMV induced a significant up-regulation of HLA-class-II-molecules, especially HLA-DR expression and an increase of apoptosis, granzyme B, perforin and IFN-γ secretion in Kasumi-1 cells cocultured with peripheral blood mononuclear cells (PBMCs). Indolamin-2,3-dioxygenase on the other hand led only to a significant dose-dependent effect on IFN-γ secretion without effects on proliferation. The addition of CpG-rich oligonucleotides and ganciclovir reversed those antiproliferative effects. We conclude that HCMV can enhance alloreactivity of PBMCs against Kasumi-1 and NB4 cells in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191482PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788343PMC
March 2018

Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Ann Hematol 2018 Feb 7;97(2):197-207. Epub 2017 Dec 7.

Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.
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http://dx.doi.org/10.1007/s00277-017-3196-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754425PMC
February 2018

Clinical Utility of Quantitative PCR for Chimerism and Engraftment Monitoring after Allogeneic Stem Cell Transplantation for Hematologic Malignancies.

Biol Blood Marrow Transplant 2017 Oct 8;23(10):1658-1668. Epub 2017 Jun 8.

Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address:

Although quantitative PCR (qPCR) has been explored for chimerism monitoring after allogeneic stem cell transplantation (SCT), evidence regarding its clinical utility compared with standard short tandem repeat (STR) is still limited. We retrospectively studied commercial qPCR and STR chimerism with respective positivity thresholds of .1% and 1% in 359 peripheral blood (PB) and 95 bone marrow (BM) samples from 30 adult patients after first HLA-matched SCT for myeloid malignancies or acute lymphatic leukemia. Concordance between the 2 methods was 79.5%, with all discordant samples positive in qPCR but negative in STR. Of the latter, sporadic qPCR positivity without clinical correlates was seen mostly in BM samples early post-transplant. In 7 of 21 patients with available follow-up samples in the first months after transplantation, qPCR but not STR revealed low levels (<1%) of sustained host chimerism in PB, reflecting delayed engraftment or persistent mixed chimerism (PMC). These conditions were associated with donor-recipient cytomegalovirus (CMV) serostatus and early CMV reactivation but not with immunosuppressive regimens or clinical outcome. qPCR predicted all 8/8 relapses with samples in the 6 months before onset by sustained positivity in both PB and BM compared with 1/8 relapses predicted by STR mainly in BM. The response kinetics to donor lymphocyte infusions for the treatment of PMC or relapse was shown by qPCR but not STR to be protracted over several months in 3 patients. Our results demonstrate the superior clinical utility of qPCR compared with STR for monitoring subtle changes of host chimerism associated with different clinical conditions, making a case for its use in the clinical follow-up of transplant patients.
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http://dx.doi.org/10.1016/j.bbmt.2017.05.031DOI Listing
October 2017

Sensitive detection of rare antigen-specific T cells directed against Wilms' tumor 1 by FluoroSpot assay.

Leuk Lymphoma 2018 02 2;59(2):490-492. Epub 2017 Jun 2.

a Institute for Transfusion Medicine, University Hospital , Essen , Germany.

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http://dx.doi.org/10.1080/10428194.2017.1330955DOI Listing
February 2018

Early CMV-replication after allogeneic stem cell transplantation is associated with a reduced relapse risk in lymphoma.

Leuk Lymphoma 2017 04 10;58(4):822-833. Epub 2016 Aug 10.

a Department of Bone Marrow Transplantation , West German Cancer Center, University Hospital Essen, University of Duisburg-Essen , Essen , Germany.

A preventive effect of early human cytomegalovirus (HCMV) replication was evaluated in 136 non-Hodgkin lymphoma (NHL) patients with mature B-cell NHLs (n = 94), and mature T- and NK-cell NHLs (n = 42) after allogeneic stem cell transplantation (alloSCT). Most study-patients (85%) had received at least 2 cycles of chemotherapy and 60% had also received an autograft prior to alloSCT. First detection of CMV-replication by HCMV antigenemia/viremia was found at a median of day +33 after alloSCT. The cumulative incidence of relapse at 5 years after alloSCT was 38% (95% confidence interval [95%CI]: 26-49) in 82 patients without compared to 22% (95%CI: 8-37) in 54 patients with HCMV antigenemia/viremia (p = .013). A decreased relapse risk of HCMV replication was confirmed by multivariate analysis for HCMV antigenemia/viremia (Hazard ratio [HR]: 0.29, 95%CI: 0.11-0.76, p < .014). This report demonstrated a possible improvement of relapse incidence after replicative HCMV infection in patients with NHL after alloSCT.
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http://dx.doi.org/10.1080/10428194.2016.1217524DOI Listing
April 2017

Cytomegalovirus replication reduces the relapse incidence in patients with acute myeloid leukemia.

Blood 2016 07 23;128(3):456-9. Epub 2016 May 23.

Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1182/blood-2016-04-713644DOI Listing
July 2016

Endoscopic and Histological Findings Are Predicted by Fecal Calprotectin in Acute Intestinal Graft-Versus-Host-Disease.

Dig Dis Sci 2016 07 19;61(7):2019-26. Epub 2016 Mar 19.

Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.

Background: Gastrointestinal graft-versus-host-disease (GI-GVHD) is a major cause of nonrelapse mortality after hematopoietic stem cell transplantation (HSCT) necessitating endoscopic examinations and biopsies for diagnosis. Fecal calprotectin (CPT) has been widely used in gastrointestinal inflammation, but comprehensive data in GI-GVHD are lacking.

Aims: We aimed to identify an association of CPT with endoscopic findings, mucosal damage and symptoms for diagnosing and monitoring acute GI-GVHD.

Methods: Symptoms were prospectively evaluated in 110 consecutive HSCT recipients by standardized questionnaires and Bristol Stool Scale (BSS). CPT was assayed by ELISA. Symptom assessment and CPT were performed weekly and with onset of first symptoms. GVHD was diagnosed according to the Glucksberg criteria and by endoscopic biopsies. Patients with GI-GVHD received standard high-dose corticosteroid therapy and follow-up CPT, and symptom evaluation was performed after 28 days. Patients not responding to steroid treatment were re-evaluated by colonoscopy.

Results: GI-GVHD was diagnosed in 40 patients. Twelve patients with GI symptoms and CMV colitis and 24 patients with isolated skin GVHD were included as control subjects. CPT was significantly higher in GI-GVHD compared to skin GVHD and CMV colitis. Endoscopic findings, histological grading, abdominal cramps, diarrhea, urgency and BSS correlated with CPT. At follow-up, CPT correlated with abdominal cramps, diarrhea, urgency and BSS. In steroid refractory patients, CPT level was still significantly associated with severity of mucosal damage.

Conclusion: CPT predicts endoscopic and histological findings in GI-GVHD and correlates with lower GI symptoms. It enables to discriminate GVHD from CMV colitis and to monitor therapeutic success.
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http://dx.doi.org/10.1007/s10620-016-4112-7DOI Listing
July 2016

CD34+ highly enriched allogeneic stem cell transplantation in a patient with mixed phenotype acute leukemia and Fusarium solani sepsis.

Ann Hematol 2016 Jan 18;95(1):155-156. Epub 2015 Sep 18.

Department of Bone Marrow Transplantation, University Hospital, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.

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http://dx.doi.org/10.1007/s00277-015-2504-yDOI Listing
January 2016

Cytomegalovirus induces apoptosis in acute leukemia cells as a virus-versus-leukemia function.

Leuk Lymphoma 2015 15;56(11):3189-97. Epub 2015 May 15.

a Department of Bone Marrow Transplantation , West German Cancer Center , Essen , Germany.

Cytomegalovirus (HCMV) reactivation occurs frequently after hematopoietic stem cell transplantation and is associated with an increased treatment-related mortality. Induction of apoptosis by HCMV is unusual because HCMV utilizes various strategies to prevent apoptosis in infected cells in order to delay cell death and maintain viral replication. Here we show that HCMV can infect the acute leukemia cell lines Kasumi-1 (AML) and SD-1 (BCR-ABL-positive ALL), which inhibited their proliferation and induced apoptosis in almost all cells after 14 days. Although HCMV induced a significant up-regulation of the anti-apoptotic gene cFLIP and the anti-stress gene Gadd45a, and simultaneously down-regulated the pro-apoptotic genes p53, Gadd45gamma in Kasumi-1 and SD-1 cells, we found that these anti-apoptotic mechanisms failed in HCMV-infected acute leukemia cells and apoptosis occurred via a caspase-dependent pathway. We conclude that HCMV can provide anti-leukemic effects in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required.
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http://dx.doi.org/10.3109/10428194.2015.1032968DOI Listing
September 2016

Methylenetetrahydrofolate reductase polymorphism has no differential effect on the outcome of allogeneic hematopoietic stem cell transplant.

Leuk Lymphoma 2015 9;56(8):2473-5. Epub 2015 Feb 9.

a Department of Bone Marrow Transplantation , West German Cancer Center, University Hospital of Duisburg-Essen , Essen , Germany.

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http://dx.doi.org/10.3109/10428194.2015.1006218DOI Listing
April 2016

Targeting bcr-abl transcripts with siRNAs in an imatinib-resistant chronic myeloid leukemia patient: challenges and future directions.

Methods Mol Biol 2015 ;1218:277-92

Faculty of Medicine, Department of Bone Marrow Transplantation, West German Cancer Center, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany,

Within the recent years, RNA interference (RNAi) has become an almost standard method for in vitro knockdown of any target gene of interest. Now, one major focus is to further explore its potential therapeutic use. From the mechanism, it becomes clear that small interfering RNAs (siRNAs) play a pivotal role in triggering RNAi. This chapter describes the in vivo application of targeted non-virally delivered synthetic bcr-abl siRNA in a female patient with recurrent Philadelphia chromosome positive chronic myeloid leukemia (CML) resistant to imatinib (Y253F mutation) and chemotherapy after allogeneic hematopoietic stem cell transplantation. A remarkable inhibition of the overexpressed bcr-abl oncogene resulting in increased apoptosis of CML cells was found. In vivo siRNA application was well tolerated without any clinically adverse events. The current findings imply that the clinical application of synthetic siRNA is feasible and safe and has real potential for genetic-based therapies using synthetic non-viral carriers.
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http://dx.doi.org/10.1007/978-1-4939-1538-5_17DOI Listing
June 2015

Neuromuscular complications after hematopoietic stem cell transplantation.

Support Care Cancer 2014 Sep 29;22(9):2337-41. Epub 2014 Mar 29.

Department of Neurology, Medical School, University of Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany,

Purpose: The aim of this study was to analyze the occurrence of neuromuscular symptoms in recipients of allogeneic hematopoietic stem cell transplantation (HSCT) for treatment of malignant hematopoietic disease.

Methods: Among 247 outpatients after allogeneic HSCT, we conducted a prospective non-interventional study between July 2011 and August 2013. During follow-up visits, clinical and electrophysiological findings were correlated to the presence of autoantibodies/alloantibodies and to frequencies of lymphocyte subpopulations in peripheral blood.

Results: Resulting in an incidence of 8.1 %, 20 patients were diagnosed with neuromuscular complications at a median onset of 12 months post-transplant. Five patients (25 %) were identified with polyneuropathy (PNP), ten patients (50 %) with combined PNP and myopathy, four patients (20 %) with myopathy or polymyositis (PM), and one patient (5 %) with myasthenia gravis (MG). Immune-mediated sensorimotor PNP after HSCT is characterized by a predominantly axonal lesion and can be overlapping with neurotoxic side effects. The latency between HSCT and development of PM varied between 60 days and 72 months. In general, PM occurs parallel to graft-versus-host disease (GvHD) after tapering of immunosuppressive medication. Typical clinical features are proximal bilateral limb weakness with muscle atrophy. Autoantibodies (Ab) were detected in 12 patients, myositis-specific Ab only in one patient. In patients with progressive neurological symptoms, a decrease in the CD4/CD8 T cell ratio was observed.

Conclusions: GvHD-related myositis appeared similar to idiopathic myositis regarding clinical and electromyographical findings. As outcome measure, sequential analysis of lymphocyte subpopulations in peripheral blood seems to be more suitable than Ab measurements. Whereas peripheral neuropathies are commonly observed shortly after HSCT, MG is a rare complication in the late post-HSCT phase.
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http://dx.doi.org/10.1007/s00520-014-2225-0DOI Listing
September 2014

A non-interventional study of the genetic polymorphisms of NOD2 associated with increased mortality in non-alcoholic liver transplant patients.

BMC Gastroenterol 2014 Jan 6;14. Epub 2014 Jan 6.

Department of General- Visceral- and Transplant Surgery, University Duisburg-Essen, Hufelandstr 55, 45 122 Essen, Germany.

Background: Infections after liver transplantation are the main cause of death in the first year. Recent reports indicate that NOD2 gene mutations increase the risk for inflammatory bowl disease and the severity of graft-versus-host disease in bone marrow transplant patients. Data on polymorphisms in liver transplant patients are sparse. We analyzed 13 single-nucleotide polymorphisms (SNPs) of 13 different gene variants including the SNPs of NOD2 genes from liver recipients. The aim of the study was to evaluate the impact of the SNPs on dialysis-dependent kidney failure, the incidence of infections and patient survival.

Methods: During a period of 20-months, 231 patients were recruited in this non-interventional, prospective study. Thirteen different SNPs and their impact on the patients' survival, infection rate, and use of dialysis were assessed.

Results: NOD 2 wildtype genes were protective with respect to the survival of non-alcoholic, cirrhotic transplant patients (3 year survival: 66.8% wildtype vs. 42.6% gene mutation, p = 0.026). This effect was not observed in alcoholic transplant recipients.The incidence of dialysis-dependent kidney failure and infection in the liver transplant patients was not influenced by NOD 2 gene polymorphisms. No effect was noted in the remaining 12 SNPs.Patients with early allograft dysfunction experienced significantly more infections, required dialysis and had significantly worse survival.In contrast, the donor-risk-index had no impact on the infection rate, use of dialysis or survival.

Conclusion: NOD2 gene variants seem to play a key role in non-alcoholic, liver transplant recipients. However these data should be validated in a larger cohort.
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http://dx.doi.org/10.1186/1471-230X-14-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890629PMC
January 2014

Maternal molecular features and gene profiling of monocytes during first trimester pregnancy.

J Reprod Immunol 2013 Sep 16;99(1-2):62-8. Epub 2013 Aug 16.

Department of Bone Marrow Transplantation, West German Cancer Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany. Electronic address:

We examined the molecular characteristics of monocytes of pregnant and non-pregnant women to investigate the molecular effects that are associated with immunoregulation at the maternal-fetal interface. We analyzed molecular features and target genes in monocytes of pregnant women using flow cytometry, real-time PCR and oligonucleotide microarray technology. CD14(high) monocytes and several immune gene members including CD200, CD200R, IDO, IFI27, IL-10 and G0S2 were found to be differentially expressed in monocytes throughout pregnancy. In addition, transcripts within components of the signaling cascade of immune cells (HLA-DRB4, HBEGF, IL-8, CD3D, CCL5), and of several transcription factors (SOCS1, CXCL10, ID1, ID2) were altered in the monocytes of pregnant women. Further studies will be needed to elucidate the biological significance of our observation.
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http://dx.doi.org/10.1016/j.jri.2013.07.001DOI Listing
September 2013

Thoughts on feto-maternal tolerance: is there a lesson to be learned from allogeneic haematopoietic stem cell transplantation?

Cell Biol Int 2013 Aug 18;37(8):766-7. Epub 2013 Apr 18.

Faculty of Medicine, Department of Bone Marrow Transplantation, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1002/cbin.10106DOI Listing
August 2013

Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis.

Haematologica 2012 Oct 4;97(10):1574-81. Epub 2012 Apr 4.

Department of Bone Marrow Transplantation, WTZ, University Hospital of Essen, Essen, Germany.

Background: Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis.

Design And Methods: We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55 ± 7.5 months.

Results: Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001).

Conclusions: The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation.
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http://dx.doi.org/10.3324/haematol.2011.061168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487559PMC
October 2012

Modulating impact of human chorionic gonadotropin hormone on the maturation and function of hematopoietic cells.

J Leukoc Biol 2011 Nov 30;90(5):1017-26. Epub 2011 Aug 30.

Department of Bone Marrow Transplantation, West German Cancer Center, Medical School of University of Duisburg-Essen, University Hospital of Duisburg-Essen, Essen, Germany.

hCG hormone is a naturally occurring, immune-modulating agent, which is highly expressed during pregnancy and causes improvements of some autoimmune diseases such as multiple sclerosis and Crohn's disease. Little is known about its immune-modulating effects. This study in MNCs of women who received hCG as preconditioning prior to IVF demonstrates that hCG increases anti-inflammatory IL-27 expression and reduces inflammatory IL-17 expression. In addition, we found increased IL-10 levels and elevated numbers of Tregs in peripheral blood of women after hCG application. Rejection of allogeneic skin grafts was delayed in female mice receiving hCG. We conclude that hCG may be useful for the induction of immune tolerance in solid organ transplantation.
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http://dx.doi.org/10.1189/jlb.0910520DOI Listing
November 2011