Hemophagocytic lymphohistiocytosis in two patients following treatment with pembrolizumab: two case reports and a literature review

Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening state of immune hyperactivation. It has the highest mortality rate among all hematological immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) when treating various cancers. However, the predisposing factors of HLH have rarely been mentioned in previous research.Case Description: Herein, we report 2 cases of HLH following treatment with pembrolizumab. A patient was diagnosed with thymic carcinoma (TC) and possible Sjögren's syndrome (SS), while another was diagnosed with non-small cell lung cancer (NSCLC) and Epstein-Barr virus (EBV) infection, and both were positive for antinuclear antibodies. Both cases experienced transient immune-related fever on day 7 after pembrolizumab administration and splenomegaly on day 10. Then recurrent high-grade fever appeared, and liver function impairment, highly elevated ferritin, and hypertriglyceridemia were tested. After the diagnosis of HLH, both patients were treated with dexamethasone and etoposide without relapse in our follow-up.Conclusions: Considering the widespread use of ICIs and the high mortality rate of HLH, the immunerelated fever, splenomegaly, and other signs of hyperinflammation after the infusion of ICIs, are worthy of attention to the presence of HLH. Preexisting autoimmune diseases (ADs) or positive antibodies, concomitant infection, and the setting of thymic epithelial tumors (TET) may be predisposing factors for HLH. And increased caution is needed before the initiation of ICIs for patients with 2 or more predisposing factors.

Haemophagocytic lymphohistiocytosis following the anti-PD-1 nivolumab in a patient with gastric cancer and ankylosing spondylitis

“…The development of autoimmunity on ICIs can predict cancer response, as indicated by the total disappearance of liver metastasis post-HLH in our patient. However, although not contraindicated, some reports showed association between pre-existing autoimmune diseases and severe irAEs [ 6 – 8 ] . The absence of the feature of haemophagocytosis in the bone marrow biopsy did not exclude the diagnosis, as haemophagocytosis can occur outside the bone marrow in the spleen and/or the liver.…”

“…Patient deceased 50-year-old female thymic carcinoma [6] Sjogren's syndrome Pembrolizumab 7 days after initiating pembrolizumab Dexamethasone and etoposide Patient survived 70-year-old male lung squamous cell carcinoma [6] Positive…”

Hemophagocytic lymphohistiocytosis/cytokine release syndrome secondary to neoadjuvant pembrolizumab for triple-negative breast cancer: a case study

“…In reviewing cases of HLH secondary to immunotherapy, we found variability in management. Some patients were treated with the HLH-2004 protocol ( 22 , 27 , 31 , 43 , 44 ), while others were treated with corticosteroids alone ( 23 , 24 , 26 , 28 , 32 , 35 , 45 – 47 ). Some centers utilized combinations of corticosteroids and other agents such as intravenous immunoglobulin (IVIG) ( 29 , 48 ), mycophenolate mofetil (MMF) and cyclosporin ( 30 ), anakinra ( 29 , 49 ), tocilizumab ( 31 , 50 ), and infliximab ( 25 ).…”

Fever of unknown origin associated with immune checkpoint inhibitors

“…One of the diagnostic criteria for HLH is the presence of a fever higher than 38.5°C. According to our review, patients with ICIs-induced HLH frequently exhibit hyperthermia, with peak temperatures ranging between 38.6°C and 40.5°C ( 115 – 117 , 124 , 130 , 131 ).…”