Severe cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report

Abstract

Background Immune checkpoint inhibitors (ICIs) have provided more options in the treatment of lung cancer. However, ICIs can cause several unfavorable reactions generally referred to as immune-related adverse effects. Case presentation In this report, we present the case of a 52-year-old woman with successful regression of pleomorphic carcinoma of the lung following nivolumab therapy. She developed purpura fulminans (PF) ultimately resulting in amputation of both lower extremities. Blood tests revealed thrombocytopenia with increased serum soluble IL-2 receptor, ferritin, and triglyceride levels suggesting hemophagocytic lymphohistiocytosis (HLH). In addition, serum A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 activity was decreased, suggesting thrombotic thrombocytopenic purpura (TTP). Further detailed analysis revealed severe hypercytokinemia including increased levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, and G-CSF. Conclusion The severe systemic inflammatory reaction and impaired peripheral circulation in this patient was attributed to excessive immunological effect induced by nivolumab resulting in cytokine release syndrome (CRS). This is the first report of a patient with multiple pathological conditions including HLH, TTP-like condition, and PF presumably arising from ICI-induced CRS. Further accumulating thoroughly investigated cases would lead to better understanding of the disease and development of reliable cancer immunotherapy.

Hemophagocytic Lymphohistiocytosis Secondary to PD-1 and IDO Inhibition in a Patient with Refractory Glioblastoma

“…We found a total of six pathology-proven cases of HLH in the setting of ICI for solid tumors, including nivolumab [3,4], pembrolizumab [5][6][7], and combined ipilimumab and nivolumab [8] (Table 1). We also found an additional five cases [4,[9][10][11] which were diagnosed based on serum findings, including elevated ferritin, soluble IL-2 receptor, triglycerides, NK cell functional assays, and cytopenias ( Table 1). The majority of patients were receiving ICI for melanoma or NSCLC (eight of 11 cases); no prior cases were described in patients with glioblastoma.…”

“…All 11 patients received steroids. Three received additional immunosuppression, including two with mycophenolate mofetil [10,11], and one with IVIG and anakinra [7]. One received etoposide according to HLH-2004 protocol [5].…”

“…Management of hematologic IRAEs including autoimmune hemolytic anemia, acquired TTP/hemolytic uremic syndrome, aplastic anemia, immune thrombocytopenia, and acquired hemophilias have been described in recent practice guidelines [2]; however, the presentation and management of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has yet to be rigorously explored or described in practice guidelines. Recently, several reports have described HLH in solid tumor patients treated with ICI [3][4][5][6][7][8][9][10][11]; these HLH syndromes varied in terms of method of diagnosis, onset, severity, and response to immunosuppressive modalities. In this case report, we describe a patient with recurrent glioblastoma who developed HLH while on a clinical trial with the PD-1 inhibitor nivolumab and a novel indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor.…”

GP130 Cytokines in Breast Cancer and Bone

“…Tocilizumab was recently approved by the FDA to treat CRS and has become the standard of care following CAR T-cell infusion [192][193][194]. It is worth noting that CRS is not exclusive to CAR T therapy and can also be triggered following treatment with immune checkpoint inhibitors [195].…”

Thrombotic thrombocytopenic purpura associated to dual checkpoint inhibitor therapy for metastatic melanoma

“…Common immune-related adverse events of this regimen comprise organ directed autoimmune phenomena as hypophysitis, pneumonitis, hepatitis, colitis, and nephritis. To our knowledge, development of an immunemediated thrombotic thrombocytopenic purpura (TTP) following ipilimumab alone or in combination with nivolumab was reported only in three cases up to date [1][2][3].…”