Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
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.
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.
To cite this abstract in AMA style:Bracaglia C, Prencipe G, Gatto A, Pardeo M, Lapeyre G, Raganelli L, Marasco E, Insalaco A, Ferlin W, Nelson R, de Min C, De Benedetti F. Anti Interferon-Gamma (IFNg) Monoclonal Antibody Treatment in a Child with NLRC4-Related Disease and Severe Hemophagocytic Lymphohistiocytosis (HLH) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/anti-interferon-gamma-ifng-monoclonal-antibody-treatment-in-a-child-with-nlrc4-related-disease-and-severe-hemophagocytic-lymphohistiocytosis-hlh/. Accessed January 22, 2018.
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