Cytokine Release Syndrome with Relative Adrenal Insufficiency Induced by Ipilimumab and Nivolumab Combination Therapy for Clear Cell Renal Cell Carcinoma

Abstract

Combination therapy with ipilimumab and nivolumab is indicated for many types of cancers; however, several patients experience immune-related adverse events (irAEs). We herein report a case of cytokine release syndrome (CRS) in a 63-year-old woman with stage IV left clear cell renal cell carcinoma. Our patient developed CRS while taking prednisolone, 43 days after the start of ipilimumab and nivolumab administration. The patient was treated with steroid pulse therapy, which improved the symptoms of shock and respiratory failure. Increased vascular permeability and relative adrenal insufficiency are considered to be the main pathogeneses. The early administration of high-dose steroids is crucial as a replacement for corticosteroids.

Introduction

Cytokine release syndrome (CRS) is a systemic inflammatory response that presents with flu-like symptoms such as a high-grade fever, fatigue, headache, rash, joint pain, and muscle pain. Severe cases show hypotension, hypoxia, renal failure, decreased platelet counts, and coagulation abnormalities (1). CRS is a common complication of chimeric antigen receptor T-cell therapy, and it often occurs within 1-2 weeks of administration. However, immune checkpoint inhibitors (ICIs) rarely lead to CRS (2). Because ipilimumab and nivolumab combination therapy is frequently used for a variety of malignancies, including renal cell carcinoma, an increasing number of patients may therefore develop CRS.

We herein report a case of CRS in a patient with clear-cell renal cell carcinoma.

Case Report

A 63-year-old woman with stage IV left clear cell renal cell carcinoma with liver and lung metastases underwent a left total nephrectomy on June X. She had a medical history of type 2 diabetes, hypertension, dyslipidemia, cough variant asthma, and early stage colon cancer, which had been treated by endoscopic submucosal dissection. In August, she received three cycles of ipilimumab (1 mg/kg) and nivolumab (240 mg/body weight) combination therapy as postoperative chemotherapy. She thereafter developed liver dysfunction due to an immune-related adverse event (irAE), with no significant symptoms in October. The patient was treated with prednisolone [60 mg (1.2 mg/kg)]. This treatment improved the liver dysfunction, and thereafter prednisolone was tapered to 30 mg at 10 mg every 5 days.

In November (day -5), the patient developed a sore throat and nasal discharge for approximately 5 days. These symptoms were considered to be associated with upper respiratory tract inflammation due to viral infection; however, the antibody titer of Epstein-Barr virus showed a pattern of a previous infection, and cytomegalovirus (CMV) antigen was not detected. On day 0, she complained of anorexia and fatigue, and had erythema on her face and trunk. Three days later (day 3), the patient developed hypotension and hypoxia. Her blood pressure was 89/55 mmHg and percutaneous oxygen saturation was 92% with 5 L/min of oxygen. Chest computed tomography (CT) revealed bilateral ground-glass opacities sparing the periphery, pleural effusions, and interlobular septal thickening (Fig. 1). Abdominal computed tomography (CT) showed ascites but no abnormal findings in the adrenal glands or other abdominal organs, such as bleeding from the adrenal glands or adrenal metastasis. Blood tests revealed elevated C-reactive protein levels, thrombocytopenia, hyponatremia, hyperkalemia, and eosinophilia. However, there were no significant changes in the liver enzyme levels. The trends in the blood test data are shown in Table 1. Electrocardiography revealed no abnormalities including ST changes. Echocardiography revealed no wall motion abnormalities or pathological valvular diseases. The central vein collapsed, with a diameter of 5 mm and minimal respiratory variation. We believe that cardiopulmonary edema is unlikely. Although the patient received 30 mg prednisolone, we assumed that the patient had a relative adrenal insufficiency based on abnormal blood test results and therefore administered 50 mg hydrocortisone. However, the effect was poor and the patient remained in shock with a blood pressure of 74/52 mmHg. Her respiratory status worsened to SpO₂ 96% after 12 L/min of oxygen administration. We suspected irAEs or severe infection and started steroid pulse therapy with methylprednisolone (500-1,000 mg daily) and the broad-spectrum antibiotic, meropenem (Fig. 2).

Figure 1.

(A) A X-ray image showed ground-glass opacities. (B) Computed tomography showed ground-glass opacities and bilateral pleural effusion.

Table 1.

Laboratory Data.

		day-14 (The date of admission)		day-1		day1		day2		day3		day4		day6
Blood chemistry
AST (U/L)		248		23		42		46		31		23		17
ALT (U/L)		323		46		49		47		39		30		28
ALP (U/L)		141		82		79		70		61		40		48
γ-GTP (U/L)		85		41		38		35		29		no data		25
Na (mEq/L)		128		133		131		127		122		123		134
K (mEq/L)		4.6		4.6		4.8		5.4		5.3		5.1		4.3
Cr (mg/dL)		0.96		0.81		0.79		0.94		0.99		0.8		0.6
BUN (mg/dL)		16		16		15		24		27		24		21
CRP (mg/dL)		7.86		0.21		2.32		6.01		4.95		2.31		0.52
ACTH (pg/mL)								7.1
Cortisol (μg/dL)								9.17
BNP (pg/mL)										5.8
Blood count
WBC (/μL)		4,800		3,970		6,750		8,550		7,550		4,900		6,210
Eo (/μL)		0		0		0		0		200		0		0
Plt (×104/μL)		256		155		82		67		81		85		125

ACTH: adrenocorticotropic hormone, ALP: alkaline phosphatase, ALT: alanine transaminase, AST: aspartate transaminase, BUN: blood urea nitrogen, BNP: brain natriuretic peptide, Cr: creatinine, CRP: C-reactive protein, Eo: eosinophils, γ-GTP: gamma glutamyl transpeptidase, K: potassium, Na: sodium, Plt: platelets, WBC: white blood cell

Figure 2.

Clinical course from the start of treatment with ipilimumab and nivolumab. The day when erythema appeared on the face and trunk is defined as day 0. BP: blood pressure, CRP: C-reactive protein, dBP: diastolic blood pressure, Eo: eosinophils, HC: hydrocortisone, Ipi: ipilimumab, K: potassium, MEPM: meropenem, mPSL: methylprednisolone, Na: sodium, Nivo: nivolumab, Plt: platelets, PSL: prednisolone, sBP: systolic blood pressure

The patient recovered from the shock, the ground-glass opacity in the lung field disappeared, and her respiratory status improved. Refilling of the third space progressed, and her urine output increased significantly. Blood test abnormalities, such as electrolyte abnormalities, eosinophilia, and decreased platelet counts, also improved rapidly. Owing to the good response to steroid pulse therapy and the absence of any imaging findings suggestive of organ-specific inflammation, we suspected CRS as a systemic irAE. The culture results for sputum, urine, and blood were later found to be negative, thus supporting our diagnosis. Maintenance therapy with prednisolone (60 mg) was administered. The prednisolone dose was reduced to 10 mg every 10 days without any symptom recurrence, and the patient was discharged on day 73.

Discussion

CRS is a systemic inflammation caused by a massive release of cytokines. Mild cases show flu-like symptoms, whereas severe cases involve kidney and liver damage, decreased blood cells, coagulation abnormalities, shock, and respiratory failure. Steroid pulse therapy and interleukin-6 inhibitors are commonly used treatments.

Although CRS is a common side effect of chimeric antigen receptor T-cells, CRS after ICI administration is rare (2), and no patients developed CRS in Checkmate 227 (3), a randomized, phase III trial with nivolumab plus ipilimumab as first-line treatment for patients with advanced non-small cell lung cancer. However, multicenter randomized phase III studies comparing pembrolizumab and platinum combination chemotherapy with nivolumab, ipilimumab, and platinum combination chemotherapy for treatment-naive advanced non-small cell lung cancer were discontinued in March 2023 because more treatment-related deaths were observed than had been expected (4). In this trial, three of the 11 deaths were due to CRS. CRS may not be as rare a side effect as previously thought and we expect that the number of patients with CRS will increase with the spread of cancer immunotherapy in the future.

CRS is difficult to diagnose CRS. We believe that echocardiography, electrocardiography, CT, and blood tests, including brain natriuretic peptide, β-D glucan, CMV antigen, antinuclear antibody, hemophagocytic imaging, and fragmented red blood cells, should be performed to make a differential diagnosis. Diseases that are common and similar in clinical presentation to CRS are heart failure and severe infection. Therefore, echocardiography and electrocardiography should be performed in addition to consultation with a cardiologist about the possibility of cardiogenic pulmonary edema or cardiogenic shock. In our case, there was no increase in the brain natriuretic peptide levels, and congestive heart failure was ruled out based on the findings of electrocardiography and echocardiography. In the early stages, it is difficult to distinguish between severe infection and CRS. Therefore, we considered the possibility of common infections, such as pneumonia, urinary tract infection, biliary tract infection, and cellulitis, based on the physical findings and imaging tests. However, it was difficult to rule out infection, and broad-spectrum antibiotics were started after performing culture tests such as blood and sputum cultures. Broad-spectrum antibiotics are used in 80% of the CRS cases (5). Other differential diagnoses include hemophagocytic syndrome, thrombotic microangiopathy, systemic lupus erythematosus, and a syndrome characterized by thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O), namely TAFRO syndrome (6). There were no hemophagocytic images or fragmented red blood cells in the peripheral blood and no abnormal findings in the antinuclear antibody or on a complement test. The lymph nodes, liver, and spleen did not become enlarged. Moreover, TAFRO syndrome was ruled out.

The median time from ICI administration to CRS onset was 11 days (5). In our case, CRS developed 43 days after the last ICI administration and prednisolone was administered. The previously reported cases of ipilimumab- and nivolumab-related CRS are shown in Table 2 (7-12). Although many cases develop within approximately 10 days of the last ICI administration, there has been a report of a case that developed 67 days later (2). In addition, five patients had already developed irAEs in other organs, and four were taking steroids before CRS development. CRS can occur after ipilimumab and nivolumab combination therapy due to viral infections, medications, or autoimmune diseases, even if time has passed since the last ICI administration and steroids are administered.

Table 2.

Case Reports of Cytokine Release Syndrome Related to Ipilimumab and Nivolumab Combination Therapy.

Reference	Age	Sex	Cancer type	Other irAEs	Steroids before CRS	Time from last ICI administration to CRS onset	Trigger
(7)	64	Female	Lung	Skin rash	PSL 20 mg	67 days
(8)	46	Female	Renal	Interstitial pneumonia	PSL70 mg	20 days	Hypersensitivity to trimethoprim/sulfamethoxazole
(9)	70	Male	Renal	Skin rash	PSL 30 mg	15 days	Dermatomyositis
(10)	55	Male	Lung	Skin rash, adrenal insufficiency	HC 20 mg	10 days	mRNA vaccination
(11)	70	Male	Lung	Isolated ACTH deficiency		4 days	COVID-19 infection
(12)	58	Female	Skin			6 days
Our case	62	Female	Renal	Liver abnormalities	PSL 30 mg	43 days	Upper respiratory tract infection

CRS: cytokine release syndrome, irAEs: immune-related adverse events, ICI: immune checkpoint inhibitor, PSL: prednisolone, HC: hydrocortisone, COVID-19: coronavirus disease 2019, ACTH: adrenocorticotropic hormone

CRS is a systemic inflammatory response with varying severities and symptoms. However, several aspects of its pathophysiology remain unknown. In the present case, two important pathologies were suggested: increased vascular permeability and relative adrenal insufficiency. Chest computed tomography revealed findings consistent with pulmonary edema. Considering the presence of pleural effusion, ascites, and collapsed central veins, we concluded that the vascular permeability had increased. Pulmonary edema and pleural effusion cause respiratory failure, and a decrease in the effective circulating plasma volume leads to circulatory failure. Increased blood pressure, increased urine volume, and improved respiratory status resulting from refilling of the third space after steroid pulse therapy also supported this hypothesis.

Adrenal insufficiency is usually unlikely to occur during the administration of 30 mg of prednisolone. However, the patient showed symptoms suggestive of relative adrenal insufficiency, including hyponatremia, hyperkalemia, eosinophilia, fatigue, and anorexia. Increased eosinophil counts at CRS onset have been reported (9). The lack of corticosteroid hormones may have contributed to the onset of shock in this case. Notably, 30 mg of prednisolone (0.6 mg/kg) or 50 mg of hydrocortisone may be insufficient owing to the high level of inflammation in CRS. Even if steroids are already being administered, high-dose steroids are considered to be important for their anti-inflammatory effects and as replacements for corticosteroids.

Our study is associated with several limitations. First, we did not measure the level of IL-6 at the peak of symptoms because our patient dramatically improved after the administration of steroid pulse therapy. Because of the wide variety of diseases to be differentiated, including sepsis, heart failure, hemophagocytic syndrome, and systemic lupus erythematosus, CRS was not suspected from the beginning. Therefore, the IL-6 levels may be helpful in diagnosing CRS. Second, the difference between cases that respond well to steroids and those that require additional immunosuppressive drugs is unclear. Our patients were able to improve with steroids alone, but there were also some patients who needed plasma exchange therapy or immunosuppressive drugs, such as tocilizumab. We look forward to further research on why steroids alone may not be effective and in addition to the development of optimal additional treatments.

In conclusion, CRS can occur even if time has passed since the administration of ICIs and steroids are already being administered, triggered by viral infections and other factors. Increased vascular permeability and relative adrenal insufficiency have been suggested to be the main pathogeneses. The early administration of high-dose steroids is crucial when treating such patients.

Written informed consent was obtained from our patients to create reports on the data and images.

The authors state that they have no Conflict of Interest (COI).