Pembrolizumab-induced Hemophagocytic Lymphohistiocytosis: an immunotherapeutic challenge

Abstract

Background: As the number of indicated malignancies for which immune checkpoint inhibitor therapy such as pembrolizumab grows the descriptions of associated immune-related adverse events (irAEs) increases as well. On rare occasions immunotherapy can lead to development of Hemophagocytic Lymphohistiocytosis (HLH) which is a potentially lethal inflammatory disorder characterized by histiocyte activation and cytokine storm. At this time no cases of HLH developing in head and neck squamous cell carcinoma (HNSCC) patients receiving pembrolizumab have been reported. Case presentation: Here we describe the first documented case of pembrolizumab-induced HLH in a 61 year-old male with metastatic HNSCC after having received multiple prior cycles of pembrolizumab without event. Following cycle 14 the patient developed fever associated with new pancytopenia and transaminitis prompting hospital admission. Infectious workup was negative, his metastatic lesions were found to be stable, and there was no evidence of new malignancy. Further workup demonstrated hyperferritinemia and bone marrow biopsy demonstrated hemophagocytosis concerning for pembrolizumab-induced HLH. Etoposide and dexamethasone therapy was initiated leading to clinical improvement and safe discharge. Conclusions: Immunotherapy is a groundbreaking therapeutic intervention for patients with malignancy, however by nature of their mechanism carry a risk of inflammatory side effects. In rare circumstances these inflammatory reactions include potentially deadly syndromes such as HLH. As immunotherapeutics such as pembrolizumab become more widely utilized increased awareness of complications such as HLH is clinically relevant.

Hemophagocytic Lymphohistiocytosis after Initiation of Combined Immunotherapy for Metastatic Melanoma

“…Basic scientists recently found a reciprocal correlation between PD-1 expression and tumor-associated phagocytic activity of macrophages as well as an enhanced cancer cell phagocytosis by macrophages following PD-1/PD-L1 targeting [9,11]. As also demonstrated in the present case, some patients with ICI-induced HLH improve with corticosteroids alone not requiring cytoreductive regimens such as etoposide [18].…”

“…Whereas causes of secondary HLH, including malignancies, infections, and autoimmune diseases, are due to an underlying condition, ICI-induced HLH has been recognized as a new clinical challenge in cancer management. Notably, HLH was also reported in patients managed with chimeric antigen receptor T-cell therapy, further highlighting the association between T-cell activity modulation and HLH development [11][12][13][14][15][16].…”

“…Supported by the current literature [1-10], we are convinced that ICI was the cause of HLH in the present case. Of course, we cannot fully exclude that HLH was mainly driven by the underlying malignancy [11][12][13][14][15][16]. However, malignancy-triggered HLH occurs most frequently in T-and NK-cell lymphoma or leukemia, diffuse large B-cell lymphoma, and Hodgkin's disease [15].…”

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

“…We reviewed 11 cases of ICIinduced HLH, including our cases (Table 3). [4][5][6][7][8][9][10][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).…”

The Immunosuppression of Etoposide Deserves Attention in Chemoimmunotherapy

“…8 In addition to this, etoposide is used to cure PD-1-induced HLH due to the effective immunosuppression of it. 9 Hematologists even recommended the therapeutic potential of low-dose etoposide when treating HLH caused by COVID-19. 10,11 By inhibiting eukaryotic DNA topoisomerase II through establishing a covalent complex with DNA, etoposide is effective as an antitumor drug.…”