A Wolf in Sheep's Clothing: Systemic Immune Activation Post Immunotherapy

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH).

Methods: All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection.

Results: Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH.

Conclusion: SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

Keywords: HLH; fever; immune checkpoint inhibitor; immune-related adverse events; systemic immune activation; toxicity.

Figure 1

(A) The pathogenesis of HLH. Known triggers include infection, malignancy, and autoimmune diseases, but also ICI therapies. Unchecked stimulation of lymphocytes (green cells indicating CD8⁺ effector cells and yellow cells indicate regulatory CD4⁺ cells) leads to hypercytokinemia, predominantly driven by interferon-γ leading to clinical symptoms. (B) CONSORT diagram demonstrating selection of patients treated with ICIs who experienced fever ≥ 38°C or chills without fever within 6 weeks of first ICI dose and attribution of causality of fever/chills. Sixteen patients with fevers were identified, of whom four had localizing symptoms (three of whom were confirmed as having fevers due to infection with positive microbiology). Of the 12 patients without localizing symptoms, four were deemed by exclusion to have an acute drug reaction, and one patient had fevers due to rapid disease progression. Seven patients were suspected to have a cytokine-mediated reaction, for which three patients met diagnostic criteria for SIA/HLH. HLH, hemophagocytic lymphohistiocytosis; ICIs, immune checkpoint inhibitors; SIA, systemic immune activation.

Figure 2

(A–C) Clinical course of three patients who confirmed SIA. Maximum temperature and ferritin levels are plotted against time from onset of ICI therapy commencement. Color bars indicate CTCAE grading (cream, Grade 1; pink, Grade 2; salmon, Grade 3+), with the thick red line indicating threshold of meeting major diagnostic criteria for SIA. Oxygen requirements have been indicated per level of FiO2 support required, with triangles representing ventilation. (A) Patient A: steroid-responsive SIA. (B) Patient B: steroid- and Tocilizumab-responsive SIA. (C) Patient C: steroid-refractory SIA. (D) Morphological features of HLH seen in patient A taken on day 4 post onset of G2 fever (top left), which are less pronounced compared with the features seen in patient C taken on day 14 post onset of fever (top right). Bone marrow aspirate (Asp) for patients A (i) and C (iii) demonstrates hemophagocytic macrophages containing erythrocytes, granulocytes, and cellular debris. Bone marrow trephine (BMT) for patient A (ii) and patient C (iv) showing hemophagocytic cells with abundant clear cytoplasm containing cellular debris. CTCAE: Common Terminology Criteria for Adverse Events; MP: methylprednisolone; SIA, systemic immune activation; ICIs, immune checkpoint inhibitors; HLH, hemophagocytic lymphohistiocytosis; IVIG, intravenous immunoglobulin.

Figure 3

Suggested clinical algorithm for managing systemic immune activation or acquired HLH in patients with cancer on immune checkpoint inhibitor therapy. Patients with mild symptoms could be treated with high-dose steroids with cytokine targeting biologics added for more severe symptoms. Patients with refractory symptoms could be considered for immunoglobulin or plasma exchange before the institution of etoposide-based chemotherapy combinations per the HLe-2004 protocol. HLH, hemophagocytic lymphohistiocytosis.