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

Abstract

Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our

Hemophagocytic Lymphohistiocytosis after Initiation of Combined Immunotherapy for Metastatic Melanoma

“…Even though the onset of HLH may occur at any time under ICI treatment, it appears that early onset of HLH is more likely. Most importantly, however, fatal outcome was reported in 16.2% of ICI-induced HLH cases -a rate that seems to be smaller than the death rates (up to 50%) reported for patients with HLH associated with other causes [1][2][3][4][5][6][7][8][9][10].…”

“…Primary or hereditary HLH (e.g., A91V mutation in PRF1) must be differentiated from secondary HLH, which is predominantly caused by infections, malignancies, and autoimmune conditions, frequently in the context of underlying immunodeficiency or immunosuppression. HLH is usually characterized by recurrent high fever, splenomegaly, pancytopenia, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, increased IL-2R, and hemophagocytosis on bone marrow assessment [1][2][3][4][5][6][7][8][9][10]. Here we report a patient with metastatic melanoma who developed HLH after initiation of anti-CTLA-4/PD-1 treatment and give a brief tabular overview on previously reported cases.…”

Two cases of lung cancer with hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors

“…We reviewed 11 cases of ICI‐induced HLH, including our cases (Table 3). 4–11 The median interval from the last dose to HLH diagnosis was 24 days; therefore, the two patients discussed in our report were diagnosed in the late phase. Based on the time interval, cases in which HLH was diagnosed after a long interval showed a lower HScore than those diagnosed after a short interval (Figure 2).…”

Secondary hemophagocytic lymphohistiocytosis due to nivolumab/ipilimumab in a renal cell cancer patient—A case report

“…Satzger et al also reported one patient (7%) treated with a combination of corticosteroids and mycophenolate motif and did well 15 . One patient in reported cases (8%) was not diagnosed on time nor received treatment resulting in death (irHLH was confirmed on autopsy) 16 . Thus far, there is no consensus on treatment for irHLH, but most patients (10/13, 77%) seem to respond well to corticosteroid monotherapy or combination therapy per HLH‐2004 protocol.…”

“…15 One patient in reported cases (8%) was not diagnosed on time nor received treatment resulting in death (irHLH was confirmed on autopsy). 16 Thus far, there is no consensus on treatment for irHLH, but most patients (10/13, 77%) seem to respond well to corticosteroid monotherapy or combination therapy per HLH-2004 protocol. All irHLH patients in the literature review who received treatment (12/13, 92%) resulted in resolution of HLH (Table 1), thus indicating an excellent prognosis with ICIs-related cases.…”