Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition — A Descriptive Observational Retrospective Multicenter Analysis
Authors: Zaremba Anne , Kramer Rafaela , De Temple Viola , Bertram Stefanie , Salzmann Martin , Gesierich Anja , Reinhardt Lydia , Baroudjian Barouyr , Sachse Michael M. , Mechtersheimer Gunhild , Johnson Douglas B. , Weppler Alison M. , Spain Lavinia , Loquai Carmen , Dudda Milena , Pföhler Claudia , Hepner Adriana , Long Georgina V. , Menzies Alexander M. , Carlino Matteo S. , Lebbé Céleste , Enokida Tomohiro , Tahara Makoto , Bröckelmann Paul J. , Eigentler Thomas , Kähler Katharina C. , Gutzmer Ralf , Berking Carola , Ugurel Selma , Stadtler Nadine , Sucker Antje , Becker Jürgen C. , Livingstone Elisabeth , Meier Friedegund , Hassel Jessica C. , Schadendorf Dirk , Hanoun Maher , Heinzerling Lucie , Zimmer Lisa 
Published: October 2021

Introduction

Immune 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.

Methods

This 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 (&lt;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+).

Results

In 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.

Conclusion

Grade 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.