Background/Purpose: Animal and humans data suggest that IFNγ plays a pathogenic role in HLH. A pilot trial in primary HLH with NI-0501, an anti-IFNγ monoclonal antibody, is ongoing. Mutations in NLRC4have recently been reported to cause recurrent macrophage activation syndrome and increased production of IL-18, that is known to induce IFNγ.

Methods: We report safety and efficacy of NI-0501 in a patient, carrying an NLRC4mutation with severe recalcitrant HLH.

Results: The patient presented at 20 days of age with fever, hepatosplenomegaly, pancytopenia, hypofibrinogenemia, hypertriglyceridemia, hyperferritinemia and sCD25 increase, meeting 6 HLH-criteria. Liver and subsequent multiorgan failure required ICU admission. Genes causing primary-HLH (PRF1, UNC13D, STXBP2, STX11, RAB27A, XIAP) and functional tests (perforin expression, degranulation assay and NK cytotoxic activity) were negative. Subsequent analysis of NLRC4 showed a de novo missense mutation (T337N) located in the same codon as that reported by Canna et al (1). Elevated serum IL-18 (>30.000 pg/ml) was documented, confirming the biologic and pathogenic relevance of the NLRC4 mutation. High-dose glucocorticoids and cyclosporine-A led to partial improvement. Development of sepsis (C.albicans and K.pneumoniae) triggered HLH reactivation. Etoposide and/or ATG were not considered because of the presence of active infections. Measurable IFNγ levels (6 pg/ml) and high levels of CXCL9 (5670 pg/ml) and CXCL10 (4400 pg/ml) were found. NI-0501 (compassionate use) was started on background dexamethasone (13.6 mg/m2) and cyclosporine-A. NI-0501 was administered every 3 and subsequently every 7 days according to pharmacokinetics. No infusion reaction was observed. Progressive improvement allowed rapid glucocorticoid tapering. After 6 months of treatment, the child is in excellent condition; all HLH parameters have normalized. Serum IL-18 levels remain elevated (32.000 pg/ml). High circulating levels (in the range of nanogram/ml) of IFNγ complexed with NI-0501, reflecting high IFNγ production, are detectable, and fully neutralized, as shown by undetectable levels of IFNγ-inducible chemokines (Table 1). He is receiving cyclosporine-A (6 mg/kg) and prednisone (0.3 mg/kg equivalent to 0.9 mg/m² dexamethasone).

Conclusion: In a patient, carrying a pathogenic NLRC4mutation with severe recalcitrant HLH, neutralization of IFNγ allowed control of all HLH features, while enabling glucocorticoid tapering.  No safety concern emerged.  

References.

1. Canna SW, de Jesus AA, Gouni S et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014 Oct; 46(10):1140-6.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-interferon-gamma-ifng-monoclonal-antibody-treatment-in-a-child-with-nlrc4-related-disease-and-severe-hemophagocytic-lymphohistiocytosis-hlh/