Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect

Abstract

Background: 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 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. Methods: We 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. Results: Finally, 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. Conclusion: With 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.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events

“…As with any form of neutropenia, ICI-related neutropenia carries an increased risk of infectious complications. 364…”

Hematologic complications of immune checkpoint inhibitors

“…The REISAMIC registry, a multicenter retrospective evaluation of three Israeli cancer centers, and two meta-analyses review case details for about three dozen total patients with ICI-associated neutropenia. 19,20,36,37 All patients suffered severe neutropenia (absolute neutrophil count [ANC] < 500/μl) or agranulocytosis within a few weeks of beginning therapy. A small percentage suffered additional ICI toxicities.…”

“…Less than 30 cases of bi-and tricytopenia are reported in the literature. [19][20][21]37 In the REISAMIC registry, 4/5 patients with pancytopenia whose bone marrow was examined showed severe trilineage hypoplasia; 1 patient's bone marrow was "nearnormal"; 1/5 died of neutropenic sepsis; and only 1/5 recovered over 8 months. 19 A summary of most of the reported cases is consistent with REISAMIC data; they report a broad range in the time of onset but usually within 2-3 months of starting the ICI, severe pancytopenia, most bone marrows examined showing severe aplastic anemia (some of which showed increased activated T lymphocytes), a low response rate (20-30%) and a comparably high death rate (5/17).…”

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

“…It can present clinically as septicemia, septic shock, and/or severe infection; however, often patients may remain relatively asymptomatic, highlighting the need for routine monitoring of neutrophil counts for high-risk drugs (Palmblad et al, 2016;Andrès et al, 2019). Drugs frequently associated with this IDR include antibiotics (e.g., cotrimoxazole and amoxicillin 6 clavulanic acid), antithyroid drugs (e.g., carbimazole), psychotropics (e.g., clozapine and carbamazepine), antiviral agents (e.g., valganciclovir), antiaggregants (e.g., ticlopidine), analgesics (e.g., metamizole), disease-modifying antirheumatic drugs (e.g., sulfasalazine), and immune checkpoint inhibitors (e.g., nivolumab and ipilimumab) Boegeholz et al, 2020). Some risk factors have been identified, such as the presence of certain HLA haplotypes.…”