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)

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Abstract

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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Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.

Dimitrios P Kontoyiannis, Kieren A Marr, Benjamin J Park … (2010)

The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

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First hospital outbreak of the globally emerging Candida auris in a European hospital

Silke Schelenz, Ferry Hagen, Johanna L. Rhodes … (2016)

Background Candida auris is a globally emerging multidrug resistant fungal pathogen causing nosocomial transmission. We report an ongoing outbreak of C. auris in a London cardio-thoracic center between April 2015 and July 2016. This is the first report of C. auris in Europe and the largest outbreak so far. We describe the identification, investigation and implementation of control measures. Methods Data on C. auris case demographics, environmental screening, implementation of infection prevention/control measures, and antifungal susceptibility of patient isolates were prospectively recorded then analysed retrospectively. Speciation of C. auris was performed by MALDI-TOF and typing of outbreak isolates performed by amplified fragment length polymorphism (AFLP). Results This report describes an ongoing outbreak of 50 C. auris cases over the first 16 month (April 2015 to July 2016) within a single Hospital Trust in London. A total of 44 % (n = 22/50) patients developed possible or proven C. auris infection with a candidaemia rate of 18 % (n = 9/50). Environmental sampling showed persistent presence of the yeast around bed space areas. Implementation of strict infection and prevention control measures included: isolation of cases and their contacts, wearing of personal protective clothing by health care workers, screening of patients on affected wards, skin decontamination with chlorhexidine, environmental cleaning with chorine based reagents and hydrogen peroxide vapour. Genotyping with AFLP demonstrated that C. auris isolates from the same geographic region clustered. Conclusion This ongoing outbreak with genotypically closely related C. auris highlights the importance of appropriate species identification and rapid detection of cases in order to contain hospital acquired transmission.

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Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.

Thomas M. Habermann, Edie Weller, Vicki A Morrison … (2006)

To address early and late treatment failures in older patients with diffuse large B-cell lymphoma (DLBCL), we designed a two-stage randomized trial of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus CHOP (R-CHOP), with a second random assignment to maintenance rituximab (MR) or observation in responding patients. Untreated DLBCL patients who were 60 years or older were randomly assigned to R-CHOP (n = 318) or CHOP (n = 314); 415 responders were randomly assigned to MR (n = 207) or observation (n = 208). The primary end point was failure-free survival (FFS). All P values were two sided. Three-year FFS rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04) at a median follow-up time of 3.5 years. Two-year FFS rate from second random assignment was 76% for MR compared with 61% for observation (P = .009). No significant differences in survival were seen according to induction or maintenance therapy. FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81) with 2-year FFS rates from second random assignment of 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively. In a secondary analysis excluding MR patients, R-CHOP alone reduced the risks of treatment failure (P = .003) and death (P = .05) compared with CHOP alone. Rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged FFS in older DLBCL patients. After R-CHOP, no benefit was provided by MR. These results, which are consistent with an additive effect of rituximab, suggest that future studies could focus on maintenance strategies with novel agents as well as new induction therapies.

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Author and article information

Contributors

Sibylle C. Mellinghoff:

ORCID: http://orcid.org/0000-0003-3928-2503

sibylle.mellinghoff@uk-koeln.de

Journal

Journal ID (nlm-ta): Ann Hematol

Journal ID (iso-abbrev): Ann. Hematol

Title: Annals of Hematology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0939-5555

ISSN (Electronic): 1432-0584

Publication date (Electronic): 7 December 2017

Publication date PMC-release: 7 December 2017

Publication date (Print): 2018

Volume: 97

Issue: 2

Pages: 197-207

Affiliations

[1 ]ISNI 0000 0000 8580 3777, GRID grid.6190.e, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), , University of Cologne, ; Cologne, Germany

[2 ]ISNI 0000 0000 8580 3777, GRID grid.6190.e, Department I of Internal Medicine, German Centre for Infection Research (DZIF), University Hospital of Cologne, , University of Cologne, ; Cologne, Germany

[3 ]ISNI 0000 0000 8653 1507, GRID grid.412301.5, Department of Oncology, Haematology, Haemostaseology and Stem Cell Transplantation, , University Hospital RWTH Aachen, ; Aachen, Germany

[4 ]ISNI 0000 0001 1091 2917, GRID grid.412282.f, Department I of Internal Medicine, Haematology and Oncology, , University Hospital Dresden, ; Dresden, Germany

[5 ]ISNI 0000 0000 8517 9062, GRID grid.411339.d, Division of Haematology and Oncology, , Leipzig University Hospital, ; Leipzig, Germany

[6 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Department of Internal Medicine–Haematology and Oncology, Mannheim University Hospital, , Heidelberg University, ; Mannheim, Germany

[7 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Department of Stem Cell Transplantation, , University Medical Centre Hamburg-Eppendorf, ; Hamburg, Germany

[8 ]ISNI 0000 0001 0482 5331, GRID grid.411984.1, Clinic for Haematology and Medical Oncology with Department for Stem Cell Transplantation, , University Medicine Göttingen, ; Göttingen, Germany

[9 ]Department I for Internal Medicine, Klinikum Frankfurt (Oder), Frankfurt (Oder), Germany

[10 ]ISNI 0000 0001 2187 5445, GRID grid.5718.b, Department of Bone Marrow Transplantation, West German Cancer Centre, University Hospital of Essen, , University of Duisburg-Essen, ; Duisburg, Germany

[11 ]ISNI 0000 0000 9935 6525, GRID grid.411668.c, Department V for Internal Medicine, , University Hospital Erlangen, ; Erlangen, Germany

[12 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Internal Medicine V, , Heidelberg University Hospital, ; Heidelberg, Germany

[13 ]ISNI 0000 0000 8517 6224, GRID grid.275559.9, Department of Haematology and Oncology, , University Hospital of Jena, ; Jena, Germany

[14 ]ISNI 0000 0004 0390 3563, GRID grid.419816.3, Department of Haematology, Oncology and Palliative Care, , Klinikum Ernst von Bergmann, ; Potsdam, Germany

[15 ]GRID grid.410607.4, Department of Haematology, Medical Oncology, and Pneumology, , University Medical Center of the Johannes Gutenberg University Mainz, ; Mainz, Germany

[16 ]ISNI 0000 0001 1378 7891, GRID grid.411760.5, Department II of Internal Medicine, , University Hospital Wuerzburg, ; Wuerzburg, Germany

[17 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Department for Haematology, Oncology and Tumour immunology, , Charité Universitätsmedizin Berlin, ; Berlin, Germany

[18 ]Department of Haematology and Oncology, Paracelsus-Kliniken Osnabrück, Osnabrück, Germany

[19 ]ISNI 0000 0000 8786 803X, GRID grid.15090.3d, Department III of Internal Medicine, , University Hospital Bonn, ; Bonn, Germany

[20 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Department of Haematology and Oncology, , University of Munich, ; Munich, Germany

[21 ]ISNI 0000 0004 0390 1701, GRID grid.461820.9, Department IV of Internal Medicine, , University Hospital Halle, ; Halle, Germany

[22 ]ISNI 0000 0000 8580 3777, GRID grid.6190.e, Clinical Trials Centre Cologne (ZKS Köln), , University of Cologne, ; Cologne, Germany

Author information

Sibylle C. Mellinghoff http://orcid.org/0000-0003-3928-2503

Article

Publisher ID: 3196

DOI: 10.1007/s00277-017-3196-2

PMC ID: 5754425

PubMed ID: 29218389

SO-VID: 0d656f0c-275b-4cc4-a160-24777f5c6442

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 7 October 2017

Date accepted : 22 November 2017

Funding

Funded by: German Society for Haematology and Medical Oncology

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ScienceOpen disciplines: Hematology

Keywords: invasive fungal infection,antifungal prophylaxis,itraconazole,fluconazole,posaconazole,amphotericin b,liposomal,isavuconazole

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ScienceOpen disciplines: Hematology

Keywords: invasive fungal infection, antifungal prophylaxis, itraconazole, fluconazole, posaconazole, amphotericin b, liposomal, isavuconazole

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)

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Most cited references 88

Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.

First hospital outbreak of the globally emerging Candida auris in a European hospital

Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.

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