The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algori
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
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Author:Caroline J. Voskens, Simone M. Goldinger, Carmen Loquai, Caroline Robert, Katharina C. Kähler, Carola Berking, Tanja Regina Bergmann, Clemens Luitpold Bockmeyer, Thomas Kurt Eigentler, Michael Fluck, Claus Garbe, Ralf Gutzmer, Stephan Grabbe, Axel Hauschild, Rüdiger Hein, Gheorghe Hundorfean, Armin Justich, Ullrich Keller, Christina Klein, Christine Mateus, Peter Mohr, Sylvie Pätzold, Imke Satzger, Dirk Schadendorf, Marc Schlaeppi, Gerold Schuler, Beatrice Schuler-Thurner, Uwe Trefzer, Jens Ulrich, Julia Vaubel, Roger von Moos, Patrik Weder, Tabea Wilhelm, Daniela Göppner, Reinhard Dummer, Lucie Heinzerling
URN:urn:nbn:de:hebis:30:3-283704
DOI:http://dx.doi.org/10.1371/journal.pone.0053745
ISSN:1932-6203
Parent Title (English):PLoS One
Publisher:PLoS
Place of publication:Lawrence, Kan.
Document Type:Article
Language:English
Date of Publication (online):2013/01/21
Date of first Publication:2013/01/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/01/21
Volume:8
Issue:(1): e53745
Pagenumber:17
Note:
Copyright: © 2013 Voskens et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HeBIS PPN:321902718
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0

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