Hemophagocytic lymphohistiocytosis: current treatment advances, emerging targeted therapy and underlying mechanisms

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Keywords: Cytokine storm; Emapalumab; Hemophagocytic lymphohistiocytosis; Pathogenic mechanisms; Targeted therapy.

Fig. 1

Timeline of the history of hemophagocytic lymphohistiocytosis (HLH). The figure illustrates the key milestones in the discovery of HLH over the past 80 years. HLH was first described in 1939, and since then, various types of primary and secondary HLH have been defined gradually. Mutations in genes associated with HLH have also been progressively discovered. CHS chédiak-higashi syndrome, GS-2 griscelli syndrome type 2, LPI lysinuric protein intolerance, X-SCID X-linked severe combined immunodeficiency, XLP-1 X-linked lymphoproliferative sisease-1, HPS-2 hermansky–pudlak syndrome 2, XLP-2 X-linked lymphoproliferative disease-2, HIDS hyper-IgD syndrome, MKD mevalonate kinase deficiency, XLA X-linked agammaglobulinemia, ALPS autoimmune lymphoproliferative syndrome

Fig. 2

Diagnostic process for hemophagocytic lymphohistiocytosis (HLH). This figure illustrates the diagnostic strategy for HLH, from initial clinical suspicion to differential diagnosis. One recent pHLH diagnostic guideline recommended incorporating functional testing of NK cells and cytotoxic T cells into the FHL diagnostic criteria, and proposed that the HLH-2004 criteria without testing NK cell function had a higher diagnostic accuracy for FHL at 99.0% (sensitivity 96.2%; specificity 99.5%) [464]. It is noteworthy that HLH can be the initial presentation of an undiagnosed malignancy, and malignancy-associated HLH typically indicates a poor prognosis [465]. The diagnosis of HLH still primarily relies on the HLH-2004 criteria, which often lack specificity in differentiating HLH from other hyperinflammatory disorders, especially in the context of malignancy. Therefore, the importance of imaging studies and biopsies should be emphasized, and all HLH patients may need to undergo tumor screening, and treating the primary malignancy is crucial for improving prognosis. MAS macrophage activation syndrome, LDH lactate dehydrogenase, EBV epstein-barr virus, PET-CT positron emission tomography-computed tomography, ANA Antinuclear Antibody, ENA extractable nuclear antigen, ANCA anti-neutrophil cytoplasmic antibody, FHL familial hemophagocytic lymphohistiocytosis, XLP X-linked lymphoproliferative disease, XIAP X-linked inhibitor of apoptosis protein, CMV cytomegalovirus, HIV human immunodeficiency virus, sJIA systemic juvenile idiopathic arthritis, SLE systemic lupus erythematosus, AOSD adult-onset still's disease, AST aspartate aminotransferase, Hgb hemoglobin, Plt platelet, Abs Neut absolute neutrophil count

Fig. 3

Schematic diagram of the pathogenesis of hemophagocytic lymphohistiocytosis (HLH). The impaired ability of natural killer cells and cytotoxic T cells to secrete perforin and granzyme results in defective clearance of target cells, leading to sustained immune cell activation and excessive production of cytokines such as interleukin-1 (IL-1), IL-6, IL-18, and tumor necrosis factor-α (TNF-α). The intense pro-inflammatory response mediated by macrophages may also be due to increased production of autoantibodies and immune complexes, resulting in abnormal immune system activation and subsequently persistent inflammatory reactions. Infections, malignancies, and immune checkpoint inhibitors can also lead to excessive immune system activation, causing hyperactivity of macrophages and T cells, which release large amounts of pro-inflammatory cytokines, resulting in a cytokine storm

Fig. 4

Schematic representation of targeted therapy for hemophagocytic lymphohistiocytosis (HLH). HLH is a syndrome characterized by excessive immune activation. Therapeutic strategies to mitigate inflammatory responses involve the inhibition of key cytokines and signaling pathways. EBV epstein-barr virus