MINI REVIEW article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders
Hemophagocytic Lymphohistiocytosis Induced by Immune Checkpoint Inhibitors: Observations and Proposed Clinical Management
Provisionally accepted
- 1Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
- 2Department of Medicine, Roswell Park Comprehensive Cancer Center, University at Buffalo, Buffalo, United States
- 3ImmunoOncology Branch, Division of Cancer Treatment and Diagnosis, National Institutes of Health National Cancer Institute, Bethesda, United States
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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.
Keywords: autoinflammatory disease, Hemophagocytic lymphohistiocytosis, HLH, Immune check inhibitor (ICI), Immune related adverse events, irAE, Toxicity management
Received: 03 Aug 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 Facchini, Switzer, Ernstoff, Puzanov and Ascierto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Paolo Antonio Ascierto
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