Hemophagocytic Lymphohistiocytosis Secondary to Immune Checkpoint Inhibitor Therapy

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a fatal systemic inflammatory syndrome. HLH has been reported as a rare immune-related adverse event (irAE) in patients receiving immunotherapy with nivolumab, ipilimumab, and/or pembrolizumab. The data are limited to case reports and case series. The objective of this research is to compile data on this rare but potentially life-threatening adverse event of immune checkpoint inhibitors (ICIs) and identify the common agents that cause this irAE, clinical spectrum, and successful management strategies to assist the treating oncologists. A review was done using PubMed database. Eligible articles included case reports and case series published from January 1, 2015, through February 1, 2021. Reports published in languages other than English were excluded. Data were compiled into a detailed supplementary table and simple descriptive analysis was used to interpret data. A total of 22 cases were included, which constituted 14 individual case reports and two case series. The immunotherapy prescribed consisted of antibodies against and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1) in all 22 patients. Out of them, immunotherapy consisting of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibodies was prescribed in nine patients. Fever was the most common symptom at the presentation (90.9%). The most common laboratory findings were anemia (90.9%), thrombocytopenia (90.9%), and elevated ferritin (90.9%). All the patients received steroids (100%). HLH responded to treatment in 19 patients. Three patients died. Three patients were rechallenged with immunotherapy, with no recurrence of HLH. HLH in the setting of ICI therapy is life-threatening, but potentially treatable with early detection. However, diagnosis is often delayed due to difficulty in differentiating the presenting symptoms and laboratory findings from complications of cancer and other therapies. Majority have shown an adequate response to standard HLH treatment; however, some required a longer course of corticosteroids. HLH is not always associated with other irAE. Rechallenging with immunotherapy was successful in some patients after completing treatment for HLH.

Haemophagocytic lymphohistiocytosis (HLH) in an adult following treatment with trimethoprim/sulfamethoxazole

“…Medicationinduced HLH is a rare entity with few prior published case reports and even fewer associated with antibiotics. [8][9][10][11][12][13] The mechanism of the association between medications and HLH is unclear and there are no established guidelines for treatment of these patients. Patients with medication-induced HLH were not specifically included in the HLH-94 or HLH-2004 trials.…”

“…The causative agent for HLH in this patient was likely TMP/SMX given the time course from the offending agent, no use of other medications, no other significant medical history and no underlying malignancy or other systemic condition identified. Medication-induced HLH is a rare entity with few prior published case reports and even fewer associated with antibiotics 8–13. The mechanism of the association between medications and HLH is unclear and there are no established guidelines for treatment of these patients.…”

The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare Immune Checkpoint Related Adverse Effects

“…A worth mentioning extremely rare adverse effect is hemophagocytic lymphohistiocytosis (HLH) as it is life threating with a high mortality rate and considered to be a serious complication [65]. Therefore, a patient presenting with severe inflammatory syndrome with associated fever, cytopenias and splenomegaly should prompt a full clinical work-up, including analysis of bone marrow aspirates and/or biopsy samples for the presence of hemophagocytic signs [65].…”

Types of Cancer and Research Covered in World Journal of Oncology

“…For instance, epidemiology was reviewed in pancreatic cancer by Rawala et al [ 1 ], in prostate cancer by Cassell et al [ 2 ] and Rawala [ 3 ], in renal cell carcinoma by Padala et al [ 4 ], and in malignant melanoma by Naik [ 5 ]. Review articles also provide an opportunity to learn about the latest updates and summaries on relatively rare conditions such as male breast cancer [ 6 ], urothelial carcinoma [ 7 ], mucoepidermoid carcinoma [ 8 ], retroperitoneal liposarcoma [ 9 ], and even on hemophagocytic lymphohistiocytosis, a relatively rare side effect of immune checkpoint inhibitor therapy [ 10 ]. There were several review articles on topics that apply to all types of cancer, such as infections in hospitalized cancer patients [ 11 ], genetic polymorphisms [ 12 ], tumor dormancy [ 13 ], and unstable psychiatric disorder [ 14 ].…”

“…In addition, we have noticed that there has been a huge increase in cancer immunology and immunotherapy interest. On immune checkpoint inhibition alone, Minami et al reported that sarcopenia and visceral adiposity did not affect its efficacy in lung cancer [ 31 ], Aly et al reported its use in sarcomatoid renal cell carcinoma [ 32 ], Tarekegn et al reported its use in relapsed/refractory classical Hodgkin lymphoma [ 33 ], Li et al reported its surrogate endpoints for gastro-esophageal carcinoma [ 34 ], and Rajapakse et al summarized one of its side effects [ 10 ]. Given the global pandemic of COVID-19 starting from 2020, our journal published three articles on this topic.…”