State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies

Abstract

Introduction: Idiosyncratic drug-induced neutropenia and agranulocytosis is seldom discussed in the literature, especially for new drugs such as biotherapies outside the context of oncology. In the present paper, we report and discuss the clinical data and management of this relatively rare disorder, with a focus on biotherapies used in autoimmune and auto-inflammatory diseases. Materials and methods: A review of the literature was carried out using the PubMed database of the US National Library of Medicine. We searched for articles published between January 2010 and May 2019 using the following key words or associations: “drug-induced neutropenia”, “drug-induced agranulocytosis”, and “idiosyncratic agranulocytosis”. We included specific searches on several biotherapies used outside the context of oncology, including: tumor necrosis factor (TNF)-alpha inhibitors, anti-CD20 agents, anti-C52 agents, interleukin (IL) 6 inhibitors, IL 1 inhibitors, and B-cell activating factor inhibitor. Results: Idiosyncratic neutropenia remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients with grade 3 or 4 neutropenia (neutrophil count (NC) ≤ 0.5 × 109/L and ≤ 0.1 × 109/L, respectively). Over the last 20 years, several drugs have been strongly associated with the occurrence of idiosyncratic neutropenia, including antithyroid drugs, ticlopidine, clozapine, sulfasalazine, antibiotics such as trimethoprim-sulfamethoxazole, and deferiprone. Transient grade 1–2 neutropenia (absolute blood NC between 1.5 and 0.5 × 109/L) related to biotherapy is relatively common with these drugs. An approximate 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g., TNF-alpha inhibitors, IL6 inhibitors, and anti-CD52 agents). Grade 3–4 neutropenia or agranulocytosis and clinical manifestations related to sepsis are less common, with only a few case reports to date for most biotherapies. Special mention should be made of late onset and potentially severe neutropenia, especially following anti-CD52 agent therapy. During drug therapy, several prognostic factors have been identified that may be helpful when identifying ‘susceptible’ patients. Older age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been identified as poor prognostic factors. Idiosyncratic neutropenia should be managed depending on clinical severity, with permanent/transient discontinuation or a lower dose of the drug, switching from one drug to another of the same or another class, broad-spectrum antibiotics in cases of sepsis, and hematopoietic growth factors (particularly G-CSF). Conclusion: Significant progress has been made in recent years in the field of idiosyncratic drug-induced neutropenia, leading to an improvement in their prognosis (currently, mortality rate between 5 and 10%). Clinicians must continue their efforts to improve their knowledge of these adverse events with new drugs as biotherapies.

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

“…Like other IDRs targeting blood and bone marrow, the time to onset of idiosyncratic drug-induced agranulocytosis (IDIAG) is usually delayed, typically between 1 and 3 months . 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).…”

Idiosyncratic Drug-Induced Neutropenia and Agranulocytosis in Elderly Patients

“…The risk of agranulocytosis is low for most of these but this risk is especially high with clozapine, thionamides (antithyroid drugs), sulfasalazine, cotrimoxazole, ticlopidine, gold salts, phenylbutazone and penicillamine [ 24 , 25 , 26 ]. In the case of antithyroid drugs, a risk of one per three users has been reported [ 27 ]. Clozapine has been described to produce agranulocytosis in about 1% of patients, especially in elderly individuals and females during the first three months of treatment [ 15 ].…”

“…Other drugs such as angiotensin converting enzyme (ACE) inhibitors, amodiaquine, histamine H2-receptor antagonists, nonsteroidal anti-inflammatory drugs, tocainide, procainamide, flecainide, aminoglutethimide, deferiprone, and dapsone have been incriminated [ 18 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In a previous study conducted in our hospital, the most frequently causative drugs were antibacterial (β-lactam and cotrimoxazole), ticlopidine, and antithyroid drugs [ 27 ]. In the Berlin Case–Control Surveillance Study (FAKOS) aimed to identify pharmaceuticals with an increased risk for this condition, the highest odds ratios were observed for clozapine, sulfasalazine, and thiamazole [ 25 ].…”

“…All biotherapies on the market, in the USA and Europe, have also been associated with neutropenia and this has been especially well documented for TNF-α inhibitors, tocilizumab, rituximab and alemtuzumab [ 37 ]. For most of these drugs, the overall neutropenia risk is estimated to be around 10%, but it appears minimal (<1%) for severe neutropenia and agranulocytosis [ 27 ].…”

Contrasting Immunopathogenic and Therapeutic Roles of Granulocyte Colony-Stimulating Factor in Cancer

“…Additional clinical indications for the therapeutic usage of rG-CSF include idiosyncratic drug-induced neutropenia and agranulocytosis, congenital neutropenic syndromes and neutropenia-associated primary immunodeficiency disorders [ 136 , 137 , 138 ]. However, the clinical utility of rG-CSF in patients with myelodysplastic syndromes (MDS) remains unclear and controversial due to the effect of this agent on malignant clones.…”