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Introduction

The prognosis of many solid tumors has improved substantially with the advent of immune checkpoint inhibitors (ICIs). However, with the new treatment, new toxicities related to the activation of the immune system have emerged, some of which can be life-threatening. Some of these potentially serious, albeit rare, immune-related adverse effects (irAEs) are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Although most frequently described in patients with hematologic malignancies treated with chimeric antigen receptor T (CAR-T) cell therapies (1), CRS has also been observed in some patients treated with ICIs (2-6), and only one report of ICANS secondary to ICIs was found (7). In the present study, the case of a patient with resected melanoma who developed clinical symptoms of CRS and ICANS shortly after initiating adjuvant treatment with pembrolizumab was reported.

Case report

A 76-year-old Caucasian male patient was admitted in November 2021 to the Doctor Peset University Hospital (Valencia, Spain) because of general malaise, chills, arthralgias, progressive weakness of proximal predominance over the last 10 days and inability to walk. He also presented with dysarthria, which started two days before admission. The patient was receiving adjuvant treatment with anti-programmed death-1 (anti-PD1) monotherapy pembrolizumab [200 mg every 3 weeks intravenously (iv)] for stage IIIC melanoma resected 3 months earlier, with the last, 4th dose of treatment administered 2 weeks before hospital admission. His medical history was positive for arterial hypertension, hypercholesterolemia and depressive disorder, for which he was taking appropriate medication. There was no history of smoking or alcohol abuse.

On physical examination, the patient was afebrile with normal blood pressure and oxygen saturation. On initial neurological examination, the patient was conscious but only partially oriented, with three failures in the Pfeiffer test, was bradypsychic, and had difficulty maintaining attention. Meningeal signs were not observed. Campimetry by confrontation was normal, as was the exploration of the cranial nerves. He presented with weakness of proximal predominance in the upper and lower limbs as well as in the neck flexors. Stretching reflexes were exalted in the upper limbs and were muted in the lower limbs. There were no alterations in the sensitivity or cerebellar exploration. Additionally, on the day after admission, he started to present with insomnia with psychomotor agitation, nocturnal confusion and delusional ideas.

On admission, his blood count was normal, however, C-reactive protein (CRP), aspartate transaminase (AST), alanine transaminase (ALT), urea and creatinine levels were increased (Table I). Hormones in the hypothalamus-pituitary-peripheral gland axis were normal. Central nervous system (CNS) imaging studies [computed tomography (CT) and magnetic resonance imaging (MRI) scans] did not reveal abnormalities nor did body CT scans. A panel of serum and cerebrospinal fluid (CSF) onco-neuronal and surface antigen antibodies were within normal limits. The CSF was clear and transparent with slightly elevated lymphocytes (8/mm3) and red blood cells (41/mm3). CSF microbiology studies were negative. Nerve conducting studies (NCS) and electromyography (EMG) (including single-fiber EMG) were normal. Analytical screening for other systemic autoimmune or inflammatory processes was also irrelevant.

Table I Maximum alterations of some laboratory tests observed during two hospital admissions due to CRS and ICANS.

Table I

Maximum alterations of some laboratory tests observed during two hospital admissions due to CRS and ICANS.

Serum parameter	Before the onset of symptoms	1st admission with CRS and ICANS symptoms	2nd admission with CRS and ICANS symptoms
Creatinine (ULN: 1.20 mg/dl)	1.29	2.0	1.59
Urea (ULN: 50 mg/dl)	42	113	92
AST (ULN: 34 UI/l)	26	71	52
ALT (ULN: 55 UI/l)	23	92	77
LDH (ULN: 243 UI/l)	188	UNK	336
CRP (ULN: 10 mg/l)	UNK	110	164
Hb (LLN: 12 g/dl)	14.1	11.9	8.5

[i] CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; ULN, upper limit of normal; AST, aspartate transaminase; ALT, alanine transaminase; LDH, lactate dehydrogenase; UNK, unknown; LLN, lower limit of normal; CRP, C-reactive protein; Hb, hemoglobin.

Under the suspicion of immune-related myopathy and encephalopathy, methylprednisolone at a dose of 1 mg/kg/day iv was initiated. After 24 h, laboratory tests revealed severe hyperglycemia without ketosis. There was a marked elevation of anti-GAD65 antibodies, and the HBA1C level was 6.03%, suggesting type 1 diabetes secondary to pembrolizumab. The results of the repeated liver and renal function tests were normal. The patient was discharged from the hospital with a tapered dose of oral prednisone over 8 weeks and insulin therapy, with complete recovery from the neurological symptoms that had led to the hospital admission. Treatment with pembrolizumab was permanently discontinued.

Two months later, while receiving a daily dose of prednisone of 5 mg, the patient was readmitted to the hospital for femoropopliteal deep vein thrombosis and bilateral pulmonary vein thrombosis. Treatment with low-molecular-weight heparin was initiated and prednisone was discontinued. A few days later, the patient started to present with neurological alterations: a generalized muscular weakness of proximal predominance and in the extensors of the neck, without sensory alteration or signs of pyramidal or cerebellar involvement. He also started to present with symptoms of encephalopathy, being once again bradypsychic, inattentive, disoriented in time, space, and personal circumstances, verbose and with a language empty of content and marked fluctuation throughout the day, with nocturnal aggravation, and subsequently with visual hallucinations. There was also a tremor of great amplitude, both at rest and in posture, without myoclonus. Repeated CNS imaging and NCS once again were normal, and electroencephalography (EEG) showed a normal path with non-specific focal irritative signs of little persistence. Laboratory tests showed elevation of AST, ALT, urea, creatinine, CRP and LDH as well as rapidly progressive normochromic-normocytic anemia with no signs of bleeding, iron or vitamin B12 deficiency, or hemolysis (Table I). There was an increased reticulocyte count and markedly elevated ferritin level; altogether, the analytical results were compatible with anemia from chronic disease. Urine tests were negative for proteinuria and hemorrhagia; consequently, immune-related nephritis was excluded. Repeated body CT tomography scan showed no liver abnormalities.

Taken together, the patient's symptoms, laboratory tests and imaging findings were compatible with ICANS in the context of CRS secondary to anti-PD1 (pembrolizumab) therapy. After restarting oral prednisone (1 mg/kg/day), there was a marked improvement in neurological symptoms over a few days, except for the symptoms related to encephalopathy that took longer to resolve. Rapid normalization of hemoglobin levels and liver and kidney function tests were also observed. Serum cytokine levels [tumor necrosis factor alpha (TNF-α); and interleukin-6 (IL-6)], which were evaluated for the first time when the patient was already on prednisone, were normal. We started to slowly taper down the dose of steroids; however, a few months later, when the patient was on 10 mg of oral prednisone daily, both TNF-α and IL-6 levels increased a few times above the upper limit of normal, and the patient once again started to present symptoms of general malaise and bradypsychia, which improved rapidly with higher doses of prednisone (Figs. 1 and 2).

Figure 1 TNF-alpha level changes according to prednisone daily dose and the moment of symptoms recurrence. Dashed line indicates the upper limit of normal. TNF-alpha, tumor necrosis factor alpha.

Figure 2 IL-6 level changes according to prednisone daily dose and the moment of symptoms recurrence. Dashed line indicates the upper limit of normal.

A few months later, a control CT scan showed lung, liver, and peritoneal metastases, and anti-BRAF and anti-MEK therapies were initiated. Unfortunately, the patient died a few weeks later due to respiratory insufficiency secondary to a syncytial virus infection.

Discussion

ICIs have unquestionably revolutionized the care of patients with malignant melanoma, in both advanced disease and adjuvant settings. However, one has to bear in mind that immunotherapy (IT) is a ‘double-edged sword’ and irAEs can affect practically any organ system, with some of them being potentially life-threatening and persisting for a lifetime. Neurological irAEs represent one of the least frequent AEs related to IT (1-5%), and although the majority of them are low-grade, some can be fatal (8,9). Neurological alterations or syndromes related to ICIs described in the literature include autoimmune encephalitis, myasthenic syndrome, myasthenia gravis, Guillain-Barré syndrome, peripheral sensorimotor neuropathies, posterior reversible encephalopathy syndrome, aseptic meningitis and transverse myelitis (10).

With the advent of CAR-T cell therapies, new toxicities have been described; some of the most serious are CRS and ICANS (1). Initially described as a systemic inflammatory response following treatment with an anti-CD3 monoclonal antibody for graft rejection after solid organ transplants, nowadays the term CRS refers to the immunological phenomenon triggered by IT (11). Although CRS is the most common serious AE of CAR-T cell therapy (about one-half of patients with 10-20% experiencing severe CRS) (12), it has also been observed, albeit very rarely (up to 1%), in patients treated with ICIs (2,4). CRS is a systemic inflammatory disease characterized by a massive release of cytokines such as IFN-γ, IL-6, IL-10, TNF-α and GM-CSF, among others (1,2,13), with IL-6 playing a crucial role in its development (5,13). It has been revealed that genetic variants in the il6 gene can cause overexpression of IL-6 through the trans-signaling pathway, potentially leading to ICI-induced CRS (6). Although higher levels of IL-6 are generally observed in patients with more severe CRS (6), there have been described patients with only a relatively small increase of IL-6 and with no difference in its levels between early and advanced stage CRS (11). On the other hand, there are other cytokines, for example, TNF-α, whose levels usually correlate with the severity of the syndrome (11).

Typical clinical symptoms of CRS include fever, constitutional symptoms such as fatigue, malaise and anorexia, and in the most severe cases, hypotension and hypoxia, accompanied by laboratory abnormalities such as cytopenia, coagulopathy, elevated liver enzymes and creatinine, and high CRP (2,13). There are different CRS-related coagulopathies, ranging from mild to severe consumptive coagulopathies to an increased risk of thrombosis (12). Only one publication of a case report of ICANS secondary to ICI-related CRS and only one case series on ICI-related CRS that refers to ICANS as the neurological toxicity of this entity were found (5,7). Nearly all patients in these reports presented with fever as a predominant symptom of CRS and a mild to moderate CRP elevation. Additionally, in most of them, the laboratory findings were positive for transaminitis, and only a minority presented with creatinine elevation and encephalopathy or hypotension according to the CRS severity. In a study of 25 individuals with ICI-related CRS, CRS-related toxicities in organ systems varied from cardiovascular (32.0%), dermatological (28.0%), gastrointestinal (36.0%), hepatic (40.0%), neurological (16.0%), pulmonary (16.0%), renal (16.0%) and rheumatic (24.0%) (5). Moreover, patients with more severe CRS presented with more cardiovascular, neurologic, pulmonary and rheumatic involvement than less severe cases. The patient in the present case report presented with chills, fatigue and arthralgias, but most importantly with neurological symptoms of encephalopathy. His laboratory findings were also typical for CRS with transaminitis, creatinine and CRP elevation. Moreover, increased serum levels of TNF-α and IL-6 have been documented, which, in our opinion, confirmed CRS in the patient.

ICANS, once considered to be part of CRS, is now considered a separate entity that can occur in any immune effector cell engaging therapy, not only CAR-T cells (1). ICANS results from endothelial dysfunction due to cytokine release, which leads to increased blood-brain barrier permeability and subsequent invasion of activated lymphocytes into the CNS with laboratory findings that may show elevated CSF leukocyte and protein counts (1). The frequency of CRS-related ICANS depends on the CRS severity, being very rare in low-grade CRS (0-7%) and affecting up to 45-50% of patients with high-grade CRS (5,6).

It´s important to distinguish between immune-related encephalitis secondary to ICIs, and ICANS which are not the same, although they share some similarities, as both involve the immune system and can affect the brain. Numerous cases of ICI-related encephalitis have been described that typically present as focal limbic or extralimibic encephalitis and meningoencephalitis, and common symptoms include fever, headache, confusion, seizures, memory problems and neurological deficits (14). On the other hand, ICANS typically manifests as toxic encephalopathy, and early findings include difficulty finding words, confusion, dysphasia, expressive aphasia, impaired fine motor skills, dysgraphia, tremor and somnolence. In more severe cases, seizures, motor weakness, global aphasia, obtundation and coma have been reported (13,15). Severe ICANS can lead to fatal intracerebral hemorrhage and malignant cerebral edema (15). Symptoms of ICANS are variable and can initially be vague, therefore its diagnosis may represent a great challenge, especially in the context of ICI therapy where this complication is extremely rare. It was considered that the patient of the present study suffered from ICANS and not other clinical conditions described as complications of treatment with ICIs, such as myositis, hypophysitis, myasthenic syndrome, or polyneuropathy. In addition, it was assumed that he did not suffer from encephalitis either since there were no alterations in any of the three tests indicative of inflammatory brain involvement: MRI, EEG and CSF studies were normal.

A workup of patients presenting with symptoms of ICANS should include CRP, a complete metabolic panel, complete blood counts and coagulation tests. Brain CT or MRI, as well as an EEG, should also be performed; while their results are non-specific for the diagnosis of ICANS, they can detect cerebral edema (1,16).

The clinical management of CRS and ICANS depends on the severity of the symptoms; low-grade CRS can be treated with supportive care and antipyretics, while moderate to severe cases, especially in patients with comorbidities and elderly, require immunosuppressive therapy such as the IL-6R-blocking antibody tocilizumab with or without corticosteroids (5,6). Tocilizumab is a humanized, immunoglobin G1κ anti-human interleukin-6 receptor monoclonal antibody that inhibits the action of IL-6, thereby reducing the inflammatory response associated with CRS. By binding to the IL-6 receptor, tocilizumab prevents IL-6 from activating its signaling pathways within cells, which are responsible for the production of pro-inflammatory molecules, and subsequently reduces the severity and duration of CRS symptoms (17). Tocilizumab selectively blocks the IL-6-related pathway of inflammation and unlike corticosteroids, it does not appear to suppress T-cell function and/or induce T-cell apoptosis, thereby preserving the efficacy of IT (17). Despite this, tocilizumab is underutilized in the treatment of CRS owing to diagnostic difficulties because the initial symptoms of CRS are non-specific and can be similar to those of sepsis or other irAEs (4,18). Additionally, there have been described patients with CRS and a relatively small increase of IL-6 in which other members of the IL-6 cytokine family induce this reaction. It is important to be aware of this as IL-6 targeting therapy may not be the optimal treatment for these patients (11). Indeed, in one case series, out of 6 patients with high-grade CRS treated with tocilizumab, 3 experienced fatal outcomes (5). However, because ICANS results from the invasion of activated lymphocytes into the CNS, it is postulated that tocilizumab has no role in its treatment and paradoxically can even worsen its symptoms (15). Therefore, corticosteroids are usually used to manage this complication because their immunosuppressive properties are necessary to quiet down overactive immune cells that invade the CNS due to cytokine storms (13,15). Tanaka et al (7) described a patient with advanced lung cancer treated with nivolumab and ipilimumab who suffered severe CRS and severe ICANS with generalized convulsions due to brain edema; after initiating steroids, the laboratory abnormalities improved rapidly, however, because of fever persistence, further immunosuppressive treatment with intravenous cyclophosphamide and immunoglobulin was required (7). In the case of the patient of the present report, we decided to start treatment with steroids as the most prominent symptoms that led to various hospitalizations were neurologic and we showed that corticosteroids are very effective in the treatment of both CRS and ICANS; however, the duration of the treatment and the optimal dose are yet to be established.

Finally, a concern regarding prolonged use of steroids which may negatively impact IT efficacy in patients with cancer remains. Numerous data showed that patients who experience irAEs due to ICIs generally have improved outcomes compared with patients without irAEs, although data are conflicting regarding the type of irAEs, tumor type and ICIs schedule (19). The possibility that the prolonged steroid use in the patient contributed to the tumor recurrence cannot be ruled out; nevertheless, treating CRS and ICANs was the priority as both are potentially life-threatening complications.

In conclusion, CRS and ICANS are potential toxicities of IT. Although most frequently observed in the treatment of hematologic malignancies with CAR-T cells and bi-specific T-cell engager antibodies, CRS has also been described in some patients treated with ICIs. The case of the patient of the present study proved that ICANS secondary to CRS may also develop in patients with solid tumors treated with ICIs. Therefore, clinicians must be aware of these potentially life-threatening complications, the importance of their emergent management and most importantly, they should always consider the risks and benefits of any IT.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study are included in the figures and tables of this article.

Authors' contributions

SO conceptualized the study, conducted comprehensive literature search, analyzed and interpreted the data and wrote and critically reviewed the manuscript. LL, DCM, AGF, CF, MDT and IMM analyzed and interpreted the data, wrote and critically reviewed the manuscript. SO and LL confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Written informed consent to publish this report was obtained from the patient's wife.

Competing interests

The authors declare that they have no competing interests.

Use of artificial intelligence tools

During the preparation of this work, the authors used AI tools in order to improve readability and language. After using these tools, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

References