Biotherapies-induced neutropenia in autoimmune and auto-inflammatory disorders and other orphan diseases

Introduction: To date, idiosyncratic neutropenia and agranulocytosis related to biotherapy (primarily TNF-alpha, anti-CD20 agents, anti-CD52 agents, interleukin (IL)-6 and IL-1 inhibitors) have been little discussed in the literature. In the present paper, both the clinical data and management of this rare disorder have been reported and discussed in the setting of autoimmune and auto-inflammatory diseases and orphan diseases. Areas covered: 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'. Authors included specific searches on several biotherapies used outside the context of oncology, including: tumor TNF-alpha inhibitors, anti-CD20 agents, anti-C52 agents, IL6 inhibitors, IL1 inhibitors and B-cell activating factor inhibitor. Expert opinion: In autoimmune and auto-inflammatory diseases or in other orphan diseases, transitory Grade 1-2 neutropenia (absolute blood NC between 1.5 to 0.5 x 10(9)/L) related to biotherapy are relatively common with these drugs. Approximately 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g. TNF-alpha inhibitors, tocizulimab, rituximab and alemtuzumab). In this setting, Grade 3-4 neutropenia (NC <= 0.5 x 10(9)/L) or agranulocytosis and clinical manifestations related to sepsis, is even more exceptional, with to date only a few case reports for the majority of biotherapies. Special mention should be made of late onset potentially severe, neutropenia, especially following rituximab and alemtuzumab therapy. In our experience, 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 case of sepsis, and hematopoietic growth factors (particularly G-CSF).