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Antifungal Chemoprophylaxis in Children and Adolescents with Haematological Malignancies and Following Allogeneic Haematopoietic Stem Cell Transplantation

Review of the Literature and Options for Clinical Practice

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Abstract

Invasive opportunistic fungal infections are important causes of morbidity and mortality in children and adolescents with cancer or haematopoietic stem cell transplantation (HSCT). Difficulties in establishing the diagnosis continue to delay antifungal therapy, and this has been shown to adversely impact on survival. Apart from ongoing attempts to improve early recognition, effective chemoprophylaxis of invasive fungal infections remains a goal of high priority in populations with disease-related incidence rates of 10% or higher. These include patients with acute myeloid leukaemia, high-risk acute lymphoblastic leukaemias, recurrent leukaemias and those following allogeneic HSCT. Incidence rates in other paediatric cancer entities, including autologous HSCT, are considerably lower and do not justify the general implementation of antifungal prophylaxis.

The difficulties in obtaining a timely diagnosis, the consequences of infectious morbidity on delaying anticancer treatment, and mortality rates >20% and >50% for invasive yeast and mould infections, respectively, provide a clear rationale for antifungal prophylaxis in high-risk populations. However, while antifungal prophylaxis has become part of infectious disease supportive care algorithms in most paediatric leukaemia and allogeneic transplantation programmes, antifungal prophylaxis remains a topic of controversy, with no clear consensus amongst different centres and groups. This is largely based on the limited paediatric data, with only a small number of meaningful studies, and on the fact that the scientific evidence for the benefit of antifungal prophylaxis has been generated exclusively by prospective, randomized, clinical phase III trials conducted in adults with comparable, but not similar conditions.

In this article, we briefly review the epidemiology of invasive fungal infections in children and adolescents with cancer and following HSCT; delineate regulatory principles of paediatric drug development with relevant examples for their successful implementation with new antifungal compounds; provide information on the pharmacology and paediatric development of current antifungal compounds; discuss for each compound the evidence for effectiveness as primary or secondary antifungal prophylaxis in adults and the pertinent data published in paediatric patients; and conclude by providing practical options for prophylaxis in children and adolescents with haematological malignancies and following allogeneic HSCT.

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Acknowledgements

No sources of funding were used to conduct this study or prepare this manuscript.

TL has received grants from Gilead; is a consultant to Astellas, Gilead, Merck, Sharp & Dohme and Schering-Plough; and has served on the speakers’ bureau of Astellas, Gilead, Merck, Sharp & Dohme and Schering-Plough. AHG has received grants from Gilead and Merck, Sharp & Dohme; is a consultant to Astellas, Gilead, Merck, Sharp & Dohme and Schering-Plough; and has served on the speakers’ bureau of Astellas, Gilead, Merck, Sharp & Dohme, Pfizer, Schering-Plough and Zeneus/Cephalon. The other authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Second Department of Pediatrics, Aristotle University, AHEPA Hospital, Thessaloniki, Greece

    Athanasios Tragiannidis & Charalampos Dokos

  2. Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children’s Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany

    Athanasios Tragiannidis, Charalampos Dokos &  Andreas H. Groll MD

  3. Department of Pediatric Hematology and Oncology, Children’s Hospital III, Johann Wolfgang Goethe University, Frankfurt am Main, Germany

    Thomas Lehrnbecher

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  1. Athanasios Tragiannidis
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  2. Charalampos Dokos
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  4. Andreas H. Groll MD
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Correspondence to Andreas H. Groll MD.

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Tragiannidis, A., Dokos, C., Lehrnbecher, T. et al. Antifungal Chemoprophylaxis in Children and Adolescents with Haematological Malignancies and Following Allogeneic Haematopoietic Stem Cell Transplantation. Drugs 72, 685–704 (2012). https://doi.org/10.2165/11599810-000000000-00000

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