Emerging immunotherapeutic approaches in hemophagocytic lymphohistiocytosis: A mini-review of novel targeted therapies

Abstract

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome are life-threatening hyperinflammatory conditions marked by uncontrolled immune activation, excessive cytokine release, and pathologic hemophagocytosis, causing multi-organ dysfunction. Traditionally classified as primary (genetic) or secondary (acquired), HLH is now understood as a spectrum of overlapping mechanisms extending to therapy-related immune toxicities such as immune effector cell-associated HLH-like syndrome. Despite diagnostic advances, HLH remains associated with high morbidity and mortality, especially in malignancy-associated cases. Standard-of-care regimens—HLH-94 and HLH-2004 protocols using dexamethasone, etoposide, and cyclosporine—remain essential but are limited by toxicity, relapse, and poor applicability to secondary forms. Over the past decade, immunotherapy has transformed HLH management. Targeted cytokine blockade with emapalumab (anti-interferon gamma), anakinra (anti-interleukin [IL]-1), and tocilizumab (anti-IL-6) shows encouraging efficacy in refractory or secondary disease. Emerging macrophage-directed therapies, including anti-CD163 and experimental strategies targeting the signal regulatory protein alpha-CD47 axis, may further modulate hemophagocytosis. Translational studies also highlight the potential of Janus kinase inhibition, checkpoint blockade, and chimeric antigen receptor T-cell modulation for refractory disease. This structured review of literature (2000-2025) across PubMed, Embase, and ClinicalTrials.gov synthesizes preclinical and clinical evidence. Our analysis indicates that while biologics offer unprecedented opportunities for personalized treatment, challenges persist due to infection risk, trigger heterogeneity, and limited randomized data. Precision medicine integrating cytokine profiling, genomic sequencing, and artificial intelligence may enable individualized therapy. Overall, immunotherapy is reshaping HLH management, but its safe, effective integration demands international collaboration, well-designed trials, and sustained translational research.

Keywords

Hemophagocytic lymphohistiocytosis / Macrophage activation syndrome / Immunotherapy / Emapalumab / Anakinra / Tocilizumab / CD163 / Signal regulatory protein alpha-CD47

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