Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition — A Descriptive Observational Retrospective Multicenter Analysis

Frontiers in Oncology

Lucie Heinzerling¹  Lydia Reinhardt²  Céleste Lebbé⁵  Barouyr Baroudjian⁵  Michael M. Sachse⁶  Alexander M. Menzies⁷  Georgina V. Long⁷  Gunhild Mechtersheimer⁸  Matteo S. Carlino⁹  Tomohiro Enokida^1,10  Makoto Tahara^1,10  Douglas B. Johnson^1,11  Paul J. Bröckelmann^1,12  Lavinia Spain^1,13  Alison M. Weppler^1,13  Carmen Loquai^1,15  Milena Dudda^1,15  Claudia Pföhler^1,16  Dirk Schadendorf^1,17  Jürgen C. Becker^1,17  Friedegund Meier^1,17  Thomas Eigentler^1,17  Katharina C. Kähler^1,18  Maher Hanoun^2,20  Adriana Hepner^2,21  Carola Berking^2,22  Rafaela Kramer^2,22  Viola De Temple^2,23  Ralf Gutzmer^2,23  Anja Gesierich^2,25  Elisabeth Livingstone^2,26  Antje Sucker^2,26  Nadine Stadtler^2,26  Selma Ugurel^2,26  Anne Zaremba^2,26  Lisa Zimmer^2,26  Stefanie Bertram^2,28  Martin Salzmann^3,30  Jessica C. Hassel^3,30 

[1] 0Department of Dermatology and Allergy, Ludwig-Maximilians-Universität (LMU), University Hospital, Munich, Germany;0Department of Dermatology, University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Dresden, Germany;0Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia;1Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia;1Université de Paris, Department of Dermatology, AP-HP Hôpital Saint Louis, INSERM U976, Paris, France;2Department of Dermatology, Allergology and Phlebology, Bremerhaven Reinkenheide Hospital, Bremerhaven, Germany;2Royal North Shore and Mater Hospitals, Sydney, NSW, Australia;3Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany;3Westmead and Blacktown Hospitals, Sydney, NSW, Australia;4Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan;4Vanderbilt University Medical Center, Department of Medicine, Division of Hematology and Oncology, Nashville, TN, United States;5Department I of Internal Medicine, Centre of Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany;5Medical Oncology Department, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;6Department of Dermatology, University Hospital Tübingen, Germany and Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Dermatology, Venerology and Allergology, Berlin, Germany;6Department of Dermatology, University Medical Center, Mainz, Germany;7Department of Dermatology, Saarland University Medical Center, Homburg, Germany;7German Cancer Consortium (DKTK), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany;8Department of Dermatology, University Hospital Schleswig Holstein, Kiel, Germany;8Department of Medical Oncology, Melanoma Institute Australia, Sydney, NSW, Australia;9Department for Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany;9Medical Oncology Service, Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil;Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC ER-EMN), Erlangen, Germany;Department of Dermatology, Mühlenkreiskliniken AöR, Ruhr University Bochum, Minden, Germany;Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany;Department of Dermatology, Venerology and Allergology, University Hospital Essen, Essen, Germany;Deutsches Zentrum Immuntherapie (DZI) , Erlangen, Germany;Institute of Pathology, University Hospital Essen, Essen, Germany;Skin Cancer Center at the University Cancer Centre Dresden and National Center for Tumor Diseases, Dresden, Germany;Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital, Heidelberg, Germany;

关键词: malignant melanoma;    immune checkpoint inhibition;    adverse events;    hematotoxicity;    neutropenia;   

DOI  :  10.3389/fonc.2021.765608

来源: DOAJ

【 摘 要 】

IntroductionImmune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia.MethodsThis multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+).ResultsIn total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4–49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia.ConclusionGrade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.

【 授权许可】

Unknown