Background/Purpose: Interferon gamma (IFNγ) plays a pathogenic role in primary and secondary HLH. An ongoing phase 2/3 trial with emapalumab in primary HLH provides encouraging preliminary data and a pilot trial in MAS in the context of sJIA has just been initiated. Gain-of-function mutations in NLRC4 are associated with a distinct autoinflammatory syndrome, with recurrent HLH.

Methods: We report safety and efficacy of emapalumab treatment in 2 patients carrying de novo missense mutations in NLRC4, with severe early onset HLH. Cytokine levels were measured by multiplex assay and by specific ELISAs and expression of IFNγin freshly isolated PBMCs by cytometry.

Results: Pt 1. Caucasian male, presented, at age 20 days, fever and rash and progressively developed clinical and laboratory features of HLH leading to multi-organ failure. A de novo missense mutation in NLRC4 (T337N) was found. High-dose glucocorticoids and cyclosporine-A (CyA) led only to partial improvement. A sepsis triggered HLH reactivation. Emapalumab was started on background of dexamethasone (13.6mg/m2) and CyA. After 3 months, the child was discharged in excellent conditions. Infections resolved during treatment with emapalumab. After 7 months of emapalumab treatment, all therapies, including emapalumab, were discontinued, without signs of HLH reactivation. Pt 2. This is 16 months old Caucasian boy with recurrent HLH and vasculitic skin lesions, since 1 month of life, secondary to a de novo missense mutation in NLRC4 (I343N). His disease was not controlled despite treatment with repeated methylprednisolone pulses and chronic daily glucocorticoid therapy, CyA and anakinra (ranging from 5 to 25 mg/kg/day). When anakinra was withdrawn prior to start emapalumab he immediately developed high-grade fever, skin rash with vasculitic lesions and diarrhea with laboratory features of HLH. Emapalumab was started on background of methylprednisolone and CyA with rapid resolution of fever and improvement in biochemical parameters. During emapalumab treatment the patient resolved his initial HLH flare and presented two HLH episodes of mild intensity controlled with moderate intensification of glucocorticoid therapy. These episodes were triggered by systemic infections caused by pathogens translocated from the gut. His diarrhea persisted with low grade inflammation; emapalumab was eventually withdrawn after 3 months. His subsequent course was characterized by additional mildepisodes of HLH. In both patients increased production of IFNγwas demonstrated by high levels of CXCL9 (pt.1: 5670 pg/ml, pt.2: 3310 pg/ml), a chemokine induced specifically by IFNγ, by increased IFNγ expression in NK cells and CD8T cells, and by presence of high levels of total IFNγ bound to circulating emapalumab.

Conclusion: In both patients, treatment with emapalumab was well tolerated, no safety concerned emerged, normalization of all HLH clinical and laboratory abnormalities was achieved. Pt. 1 showed no disease reactivation even in the absence of treatments In pt. 2 IFNγ neutralization has provided control of HLH, while his underlying disease and, in particular, gut inflammation and gut colonization by MDR pathogens remained unchanged.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/emapalumab-an-anti-interferon-gamma-monoclonal-antibody-in-two-patients-with-nlrc4-related-disease-and-severe-hemophagocytic-lymphohistiocytosis-hlh/