Abstract
BackgroundCancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial.MethodsWe present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search.ResultsFinally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia.ConclusionWith an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.
Highlights
Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types
As the overall incidence of neutropenia as immune-related adverse events (irAEs) in cancer patients treated with ICI-therapy is low [8], only a few articles with patient data are available in the literature [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]
We present the clinical course of two patients who were given this particular drug combination, with the documented reproducible irAE of severe neutropenia due to the ICI therapy in one of the cases
Summary
Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The treatment procedure of irAE consists of discontinuation of the ICI therapy and administration of corticosteroids [34] This therapy regimen could be contraindicated for patients with severe neutropenia, as the application of corticosteroids in this context might further increase the risk of infection [35]. The treatment of drug-induced neutropenia consists of G-CSF and, if signs of infection are present, empiric antibiotic treatment with reconstitution within a few days [36] Several countries, such as the United States and the United Kingdom, have withdrawn metamizole from the market due to this adverse side effect. We supplement this report with a retrospective clinical data analysis of published clinical courses of patients with neutropenia as irAE after ICI treatment
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