Hemophagocytic lymphohistiocytosis induced by immune checkpoint inhibitors: observations and proposed clinical management

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory disease caused by an overactivation of immune cells. Its low incidence and broad range of clinical signs and symptoms may mimic more common inflammatory and/or infectious processes, causing delays in accurate diagnosis and management with a resultant negative impact on clinical outcomes. A subtype of HLH triggered by immune-activating therapies or drug hypersensitivity (Rx-HLH) has been observed after exposure to immune checkpoint inhibitors (ICIs), whose pathogenesis may be related to the dysregulation between cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). The mainstay of HLH treatment involves aggressive supportive care, addressing the underlying triggers, ruling out alternative causes, and prompt incorporation of immunosuppressive and/or immunomodulatory agents in order to prevent fatal multi-organ damage. A multidisciplinary approach is critical. Here, we provide a perspective summary of the currently understood pathophysiology of ICI-induced Rx-HLH and a proposed algorithmic approach for clinical management based on expert opinion supported by current literature and examples from clinical practice.