ReviewClinical Medicine Insights. Oncology2026
Immune Checkpoint Inhibitor-Associated Hemophagocytic Lymphohistiocytosis: A Systematic Review.
Review in Clinical Medicine Insights. Oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Authors and funding
6 authors.
Funding
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Abstract
Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory toxicity increasingly reported with immune checkpoint inhibitors (ICIs). We systematically reviewed published cases of ICI-associated HLH to characterize presentation, diagnostic patterns, treatment, outcomes, and rechallenge experience. Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to 10 March 2026 according to a prior protocol. English-language case reports and case series reporting ICI-associated HLH or macrophage activation syndrome with extractable patient-level data were included. Data were synthesized descriptively. The review was retrospectively registered with the Open Science Framework (OSF; DOI: 10.17605/OSF.IO/6ARJC). Results: Ninety-six patients from 78 reports were included: 65 case reports and 13 case series. Median age was 60.0 years (IQR, 42.5-72.0; range, 2-86), and 53 patients (55.2%) were male. The most common malignancies were melanoma (27.1%), lung cancer (24.0%), breast cancer (9.4%), and kidney cancer (8.3%). Among reported cases, PD-1 blockade was the most common ICI exposure (60/96, 62.5%), followed by mixed-class regimens (20/96, 20.8%). HLH occurred after a median of 2 ICI cycles and 30 days from ICI initiation.Diagnostic ascertainment was heterogeneous: combined criteria were used in 31/96 patients (32.3%), HLH-2004 criteria in 27/96 (28.1%), HScore in 23/96 (24.0%), and clinician diagnosis in 15/96 (15.6%). Fever occurred in 94/96 patients (97.9%), cytopenias in 91/93 (97.8%), and ferritin was markedly elevated where reported, with a median of 10,450 ng/mL. Corticosteroids were administered in 96/96 patients (100%), whereas etoposide was used in 19/96 (19.8%), IL-6 blockade in 21/96 (21.9%), and IL-1 blockade in 10/96 (10.4%). Clinical improvement or resolution occurred in 78/94 patients (83.0%). Death occurred in 24/95 patients (25.3%). ICI rechallenge was reported in 7 patients, with recurrent HLH in 3. Conclusion: ICI-associated HLH should be considered early in ICI-treated patients presenting with fever, cytopenias, and marked hyperferritinemia. Published cases show heterogeneous diagnostic ascertainment, variable treatment escalation beyond corticosteroids, and substantial mortality, underscoring the need for standardized diagnostic workup, early multidisciplinary management, and cautious individualized decisions regarding ICI rechallenge.
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