https://orcid.org/0000-0002-8707-0487
ABSTRACT
Objective:
An association exists between immune checkpoint inhibitors and hemophagocytic lymphohistiocytosis (HLH). Therefore, the main objective of this study was to collect data on this rare but potentially life-threatening immune-related adverse reaction to identify the medications that cause it, the clinical characteristics, and effective treatments.
Methods:
Literature in English and Chinese on immune checkpoint inhibitors causing HLH published from August 2014 to March 2024 was analyzed. Immune checkpoint inhibitors, immunotherapy, anti-PD-1, PD-L1 inhibitors, HLH, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome keywords were used to find the literature on China Knowledge Network, Wanfang, PubMed and Emabase Databases.
Results and discussion:
Twenty-four studies were included, with a total of 27 patients (18 males and 9 females) with a mean age of 58 years (range 26–86). The mean time to the onset of symptoms was 10.3 weeks (7 days–14 months). The main clinical characteristics were fever, cytopenia, splenomegaly, methemoglobinemia, hypofibrinogenemia, and bone marrow biopsy showed phagocytosis. Twenty-two patients improved after the treatment with steroids, cytokine blocking therapy and symptomatic treatment, four patients died, and one patient was not described.
Conclusion:
HLH should be not underestimated as a potentially serious adverse effect of immune checkpoint inhibitors since appropriate treatments may save the life of patients.
1. Introduction
Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a life-threatening syndrome caused by an excessive inflammatory response due to multiple causes, mostly by macrophage and T cell activation leading to a massive cytokine release. It consists of two main types: primary and secondary [Citation1, Citation2]. Primary HLH is mainly caused by defective cytolytic function of cytotoxic T cells or natural killer (NK) cells, whereas secondary HLH is mainly due to the intense immune activation of the immune system and is caused by severe infections, malignancies, and autoimmunity [Citation3]. Since HLH is not always recognized or clinicians are late in recognizing it, this increases the risk of death, especially in adults; therefore, timely diagnosis and treatment are crucial [Citation4].
According to the latest HLH-2004 diagnostic and therapeutic guidelines from the Histiocyte Society, patients who meet the diagnostic criteria consistent with molecular markers for HLH do not necessarily have to fully meet the clinical diagnostic criteria for HLH, and the remaining patients should meet five of the following eight characteristics: 1. Fever. 2. Splenomegaly, 3. Hematopenia affecting at least two of the three population spectra of the peripheral blood. 4. Hypertriglyceridemia and/or hypo fibrinogenemia. 5. Phagocytosis of the bone marrow, spleen, or lymph nodes. 6. Low or absent NK-cell activity. 7. Methemoglobinemia. 8. High levels of sIL-2R [Citation5]. Emerging adulthood patients with HLH do not always show a detectable NK cell activity and sIL-2R levels; thus, at this point clinicians should not wait that the patients meet HLH 2004 criteria before treating them [Citation6]. In addition, some clinicians apply the HScore scoring system to assess the diagnostic relevance and risk probability of hemophagocytic syndrome, which bases the evaluation on nine variables (i.e. known potential immunosuppression, hyperthermia, organomegaly, triglycerides, ferritin, serum glutamate oxaloacetate aminotransferase, fibrinogen levels, hemocytosis, and characteristics of phagocytosis on bone marrow aspirates) [Citation7]
Immunotherapy has currently become one of the emerging approaches in the treatment of malignant tumors, with proven efficacy on a wide range of tumors. It is mainly divided into active immunotherapy and passive immunotherapy, while immune checkpoint inhibitors (ICIs) are a new approach to perform immunotherapy [Citation8]. Instead of simply enhancing the body immune function and having no antigen dependence, they eliminate programmed death protein-1 or L1 and cytotoxic T-lymphocyte-associated protein-1 (CTLA-4) by inhibiting them to enhance the anti-tumor activity and to prevent tumors from escaping cellular immunity [Citation9, Citation10]. Previous studies on adverse drug reactions focused on the analysis of case reports and alert databases of HLH caused by ICI therapy, confirming that it is one of the main etiological factors in the treatment of malignant tumors [Citation11, Citation12]. The present study collected data on such rare but life-threatening immune-related adverse effects (irAE) in patients to identify drugs with common clinical features and effective treatment strategies, with the aim of exploring the potential association between the clinical benefits in patients suffering with oncologic diseases and HLH, and to inform clinicians of potential new treatments.
2. Methods
Chinese and English databases including Wanfang, China VIP Database, PubMed, and Emabase were used to search articles on ICI-induced HLH from August 2014 to March 2024, including case reports, case series, and clinical studies. Keywords included immune checkpoint inhibitors, immunotherapy, anti-PD-1, PD-L1 inhibitors, HLH, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome. Duplicate studies, mechanistic studies, reviews, guidelines, unavailability of full text and incomplete data were excluded. Patient information was extracted and collected, including gender, nationality, medical history, comorbidities, indications of HLH diagnosis and irAEs, time of onset, clinical presentation, laboratory tests, blood cells, ferritin, triglycerides, fibrinogen, liver function, lactate dehydrogenase, CD25, NK cells, hepatosplenomegaly, liver biopsy, bone marrow biopsy, treatments, and outcomes.
The diagnostic criteria for HLH-2004 and HScore are shown in [Citation5] and [Citation7].
Table 1. Diagnostic criteria for HLH – 2004 criteria.
Table 2. Diagnostic criteria for HScore.
3. Results
A total of 173 case reports were collected by keywords, 149 were excluded (41 duplicates, 29 reviews, 5 mechanism studies, 7 guidelines, 9 because of unavailable full text, 53 because of content inconsistency, and 5 because of incomplete data), and 24 articles were included in this study.
Clinical information with haemophagocytic lymphohistiocytosis induced by ICI in [Citation13–36].
Table 3. Clinical information with haemophagocytic lymphohistiocytosis induced by ICI.
3.1. Clinical information
The 24 studies included 27 patients, (18 males and 9 females) with a median age of 58 years (range 26-86). Among them, 9 were from North America, 9 from Asia, 8 from Europe, and 1 from South America. Immunotherapy was used to treat melanoma (n = 11, 40.7%), renal cell carcinoma (n = 2, 7.4%), lung cancer (n = 8, 29.6%), cervical cancer (n = 1, 3.7%), breast cancer (n = 1, 3.7%), Hodgkin lymphoma (n = 1, 3.7%), Kaposi's sarcoma (n = 1, 3.7%), prostate cancer (n = 1, 3.7%) and bladder cancer (n = 1, 3.7%). Four patients had a past medical history of hypertension, coronary artery disease, impaired glucose tolerance [Citation16], rheumatoid arthritis [Citation24], psoriasis [Citation26], and immune thrombocytopenic purpura [Citation28].
3.2. Immunotherapy dosing regimen
Individual medications included nivolumab (n = 6, 22.2%), pembrolizumab (n = 8, 29.6%), and atezolizumab (n = 1, 3.7%). Combination therapies included nivolumab with ipilimumab (n = 10, 37.0%), pembrolizumab with bevacizumab (n = 1, 3.7%), and nivolumab with brentuximab vedotin (n = 1, 3.7%). The mean time to HLH onset was 10.3 weeks (7 days–14 months), most commonly within one month of the first dose. Six patients developed the following adverse reactions: purpura fulminans (n = 1, 3.7%), autoimmune hemolytic anemia (n = 1, 3.7%), rash (n = 1, 3.7%), autoimmune encephalitis (n = 1, 3.7%), interstitial pneumonia and Stevens-Johnson syndrome (n = 1, 3.7%), as well as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN)-like eruption (n = 1, 3.7%).
3.3. Clinical manifestations
15 patients met the HLH-2004 diagnostic criteria (5 out of 8 criteria), 2 had atypical HLH (4 out of 8 criteria), and 22 met the diagnostic relevance score HScore > 168 (51.2%) (the mean of the available: 212, mean probability: 77% ± 10%). Eleven patients showed signs and symptoms consistent with HLH, including fever (n = 26, 96.3%), splenomegaly (n = 10, 37.0%), hepatosplenomegaly (n = 6, 22.2%), thrombocytopenia (n = 23, 85.2%), diphtheria (n = 10, 37.0%), pancytopenia (n = 9, 33.3%), hyperferritinemia (n = 26, 96.3%), hypertriglyceridemia (n = 13, 48.1%), hypofibrinogenemia (n = 15, 55.6%), low or absent NK cells (n = 2, 7.4%), and high soluble CD25 (n = 3, 11.1%). Bone marrow biopsy from 14 (51.9%) patients revealed phagocytic activity, and 1 (3.7%) liver biopsy revealed phagocytic activity.
In addition to the above symptoms, these patients showed other symptoms such as headache (n = 1, 3.7%), generalized fatigue, weakness and discomfort (n = 8, 29.6%), dizziness (n = 1, 3.7%), diarrhea (n = 1, 3.7%), vomiting (n = 2, 7.4%), papules (n = 2, 7.4%), and skin rash (n = 2, 7.4%).
Thrombocytopenic patients had a mean value of platelets of 65× 109/L (11–114 × 109/L, reference value: < 100 × 109/L), patients with leukopenia had a mean value of white blood cells of 1.94 × 103 /µL (1.1–2.71 × 103/µL), a mean value of hemoglobin of 66 g/L (29–120 g/L, reference value: < 90 g/L), mean ferritin level of 29899 µg/L (20.406–64726 µg/L, reference value: > 500 µg/L), mean triglycerides of 399.11 mg/dl (105.34–1821.15 mg/dl, reference value: ≧ 265 mg/dl), mean fibrinogen level of 1.61 g/L (0.5–4.97 g/L, reference value: < 1.5 g/L), with an average level of lactate dehydrogenase of 1434 U/L (792–4186 U/L).
3.4. Treatment and outcome
Among the HLH patients, all were treated with steroids, 4 received etoposide, 5 received cytokine blockade (4 with tocilizumab and 1 with anakinra), 5 received immunosuppressive therapy (3 mycophenolate mofetil, 1 tacrolimus, and 1 ciclosporin), and 1 received antibiotics (posaconazole, and caspofungin).
Among the HLH patients, 22 recovered, 4 died, and the final outcome of 1 was unknown. As regards HLH patients with primary disease, 6 were in complete remission, 7 were in partial remission, 4 died, 1 developed new metastasis, and the final outcome of 9 was unknown.
4. Discussion
A comprehensive analysis of hematologic adverse effects associated with the use of ICIs in this study revealed that melanoma and lung cancer were the main diseases among HLH patients. However, new cases of HLH have now been gradually identified, which include patients originally suffering with some previously unrecognized diseases such as cervical cancer and Hodgkin's lymphoma. This demonstrates that the prevalence of ICI-induced HLH problems is mainly among oncologic patients. In addition, the mean age of patients at the onset of ICI-induced HLH was approximately 58 years, with a higher incidence in men, which is consistent with previous findings [Citation11, Citation12, Citation37], probably because of the high prevalence of cancer and the incidence of immune-related HLH in men [Citation38, Citation39]. In addition, 15 patients met the HLH-2004 diagnostic criteria (5 out of 8 criteria), 2 had atypical HLH (4 out of 8 criteria), and 22 met the diagnostic relevance score HScore > 168 (51.2%), which help physicians in the estimation of the individual risk of developing reactive phagocytic syndrome [Citation40]. In terms of patient presentation, our results reported splenomegaly (10 patients), hepatosplenomegaly (6 patients), low or no NK cells (2 patients), methemoglobinemia (26 patients) and high soluble CD25 (3 patients). Previous studies reported that the combination of high soluble CD25 and ferritin is an optimized indicator of inflammation in HLH predicting mortality; however, this indicator in clinical practice is not widely used [Citation41]. In addition, bone marrow biopsy showed phagocytic activity in 10 patients, while liver biopsy showed phagocytic activity in one patient. These results represented the main markers in the HLH scoring criteria and might have an impact on our differential diagnostic results [Citation42].
Immunotherapy is gradually been chosen to cure a variety of malignancies, and this work reported that 10 patients used a combination therapy of nivolumab with ipilimumab; ICI blockade leads to the overactivation of CD8+ T cells, whereas PD-1/PD-L1 blockade enhances macrophage-mediated phagocytosis of tumor cells [Citation43]. In addition, CTLA-4 inhibition removes or modulates Treg cells and their role in tumor microenvironment, resulting in systemic irAE [Citation44], while the use of the two together (anti-PD-1 blockers and anti-CTLA-4 blockers) improves antitumor efficacy, although the risk of adverse effects is increased. In contrast, the use of antiangiogenic drugs inhibits T cell function, increases Tregs and myeloid-derived suppressor cells (MDSCs), and inhibits the differentiation and activation of DCs. Several studies also showed that the use of bevacizumab in combination with PD-1 monoclonal antibodies increases the risk of serious adverse reactions in patients with malignant tumors [Citation45–47]. It is yet not clear if an excessive inflammatory response is triggered by brentuximab vedotin alone or in combination with nivolumab. A study analyzing the WHO Global Case Safety Reporting Database showed that 90% of cases mentioned ICI as the only suspected drug.
However, three of the patients in our reported cases had prior rheumatoid arthritis (cured), psoriasis (cured), and immune thrombocytopenic purpura (died patient). Notably, previous studies showed that patients having autoantibodies (antinuclear, antineutrophil cytoplasmic, antithyroid antibodies, and rheumatoid factor) as biomarkers of the risk of developing hematologic or other immune-related toxicities are at a higher risk of irAE that patients without these autoantibodies [Citation48, Citation49]. In addition to ICI drug factors, cancer progression, infectious factors, and genes with potentially genetic factors and HLH-related genes (e.g. germline polymorphisms in perforin-1 PRFA91 V) are also important for inducing HLH [Citation50].
ICIs can be used to treat HLH caused by other factors, and navulizumab restores the expression of HLH-associated degranulation and co-stimulatory genes in CD8+T cells, thus representing a potential cure for relapsed/refractory EBV-HLH [Citation51]. The combination with rituximab is effective in treating EBV-HLH and maintaining EBV-infected T and B whole lineage lymphocytes [Citation52].
Cytokine release syndrome (CRS) is a systemic inflammatory response triggered by a massive release of cytokines in the blood stream by immune cells [Citation53], resulting in a cytokine storm and a state of hyperinflammation, potentially progressing to organ failure and HLH-like symptoms in extremely severe cases. Patients usually show a variety of clinical symptoms at the onset of CRS such as fever, hypotension, and tachycardia, which may even worsen in as little as 1 hour. The distinction between primary HLH, secondary HLH and CRS is challenging since CRS characteristics may overlap those of HLH [Citation54]. Histopathologic evidence of hepatosplenomegaly and phagocytosis are performed to allow the diagnosis of HLH [Citation55]. According to ASCO guidelines, tocilizumab can be used in the treatment of low-grade CRS, while corticosteroids can be used in the treatment of refractory, long-term, or high-grade CRS. In addition to tocilizumab, alternative IL-6 antagonists (e.g. cetuximab and crizanlizumab) are used in the treatment of refractory CRS, whereas anabolic acid may alleviate the symptoms of intermediate and high-grade CRS in patients receiving CAR T-cell therapy [Citation56]. Notably, early diagnosis and treatment are particularly important in patients with either CRS or HLH.
Currently, applicable protocols for the treatment of HLH in adults are lacking. According to the latest guidelines of the European League Against Rheumatism/American College of Rheumatology, immunomodulatory therapeutic agents such as glucocorticoids, recombinant IL-1 receptor antagonists, anabolic agents and intravenous immunoglobulins are available for patients with high-risk characteristics or progressive or suspected HLH/MAS. The more effective etoposide should be considered when upgrading the therapy or considering treatment options applicable to a particular situation, when the patient clinical context needs to be fully integrated into the program. Treatment with high-dose glucocorticoids and/or other drugs such as cyclosporine, ruxolitinib, emapalumab, and rituximab should be considered for patients with increased inflammation or worsening organ damage after early immunomodulatory therapy after consulting with experts [Citation57]. In addition, appropriate anti-infective and antiviral drugs should also be administered according to the condition of the patient. Inflammatory biomarkers should be closely monitored (e.g. CRP and ferritin), organ damage indicators (e.g. complete blood count, fibrinogen, and ALT), and any drug-specific monitoring during the treatment, which should be more frequent in critically ill patients.
Interestingly, our report revealed that among the 81.5% of patients with HLH, 14.8% died; 48.14% of patients with HLH as original disease experienced remission of their tumors. Our hypothesis was that the treatment of HLH could positively influence the original tumor to go into remission. Takeshita M et al. found that tumor regression occurred simultaneously to immunotherapy-induced HLH by treating a patient suffering from non-small cell lung cancer with nabulizumab [Citation58]. In addition, several retrospective studies demonstrated that patients with tertiary and higher degrees of immune adverse response have higher remission rates and disease control rates [Citation59], with a significantly longer median survival [Citation60], suggesting a strong association between the occurrence of irAE and endpoints, such as clinical efficacy. Nevertheless, these studies were retrospective, and the number of cases was small; thus, further studies are needed to investigate the mechanisms involved to provide the most effective and safe treatments for patients.
Some limitations are present in this study; it is a retrospective analysis of previously published case reports and lacks some data such as time to HLH regression.
5. Conclusion
HLH is caused by an excessive and uncontrolled inflammation, and clinicians should individualize the treatment of HLH, observing and evaluating the patient's clinical manifestations and organ function frequently and in more detail, to avoid wasting time due to a delayed diagnosis, and to consider the possibility of adverse events.
Conflicts of interest
Zhiya Xu – has no relevant conflicts of interest.
Huilan Li – has no relevant conflicts of interest.
Xinyi Yu – has no relevant conflicts of interest.
Jia Luo – has no relevant conflicts of interest.
Zanling Zhang – has no relevant conflicts of interest.
Conflicts of interest
All authors declare no competing interests.
supplementary document.docx
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The authors thank all people who contributed to this work.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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