Personalized treatment of immune checkpoint inhibitor-related severe hemophagocytic lymphohistiocytosis (HLH).

Abstract

e15079 Background: HLH is a rare but potentially lethal immune related adverse event (irAE) with an incidence of 0.03-0.4 % in cancer patients undergoing immune checkpoint inhibition (ICI). Given the rarity of HLH there are currently no diagnostic or therapeutic guidelines and the majority of the reported cases have been treated with corticosteroids alone with very variable response rates. There is currently no established therapy for corticosteroid resistant HLH occurring in the context of immunotherapies. We investigated the treatment possibility of severe HLH according to the cytokine profile. Methods: We report the clinical presentation, the cytokine profile and the outcome of three melanoma patients with ICI-related HLH not responding to high dose corticosteroid therapy alone who were treated with additional anti-IL-6R at the Centre Hospitalier Universitaire Vaudoise. We collected the following data: treatment setting, ICIs received, duration of each treatment, HLH criteria, bone marrow biopsy, cytokine profile, response to corticosteroid and to anti-IL-6R therapy. Results: We identified a severe HLH in three metastatic melanoma patients treated with ipilimumab and nivolumab for 2 of them and 1 with pembrolizumab. HLH occurred in a median of 10 weeks after initiation of immunotherapy. The patients met at least five of the HLH-2004 criteria including high ferritin levels ( > 100.000 ng/ml). High levels of interferon-gamma (IFNγ), IFNγ-induced chemokines, particularly CXCL9, CXCL10, CXCL13, IL-18 and IL-6 were found in all patients. For 2 of them we identified a highly infiltrated bone marrow by activated CD8+ T and NK cells. Median duration of corticosteroids therapy was 6.5 weeks. The evolution of the three patients was rapidly favorable in a median of 2.5 weeks after the addition of an anti-IL-6R therapy targeting the IFNγ/Th1 axis. Conclusions: HLH is a potentially life-threatening irAE necessitating emergency therapy. CXCL9 and Th1 cytokines are markedly elevated in patients with ICI-related HLH due to the activation of the IFNγ pathway. High CXCL9 and Th1 cytokines levels appear to be potential specific biomarkers for ICI-related HLH diagnosis. Blocking this axis by anti-IL-6 therapy seems a very promising strategy for severe ICI-related HLH allowing rapid resolution of symptoms and normalization of the abnormal laboratory results.