Tocilizumab, an IL6-receptor antibody, proved effective as adjuvant therapy for cytokine storm induced by severe infection in patients with hematologic malignancy

Abstract

Patients with hematological malignancies who experience severe infections are at risk of developing dangerous complications due to excessive inflammatory cytokines. To improve the prognosis, it is crucial to identify better ways to manage the systemic inflammatory storm after infection. In this study, we evaluated four patients with hematological malignancies who developed severe bloodstream infections during the agranulocytosis phase. Despite receiving antibiotics, all four patients presented elevated serum IL-6 levels as well as persistent hypotension or organ injury. Adjuvant therapy with tocilizumab, an IL-6-receptor antibody, was administered, and three of the four patients showed significant improvement. Unfortunately, the fourth patient died due to multiple organ failure caused by antibiotic resistance. Our preliminary experience suggests that tocilizumab, as an adjuvant therapy, may help alleviate systemic inflammation and reduce risk of organ injury in patients with elevated IL-6 levels and severe infection. Further randomized controlled trials are needed to confirm the effectiveness of this IL-6 targeting approach.

Introduction

Severe infections pose a significant threat during chemotherapy or hematopoietic stem cell transplantation. During infection, excessive systemic inflammation and elevated cytokine levels due to dysregulated host immune responses are associated with negative clinical outcomes [1–3]. IL-6 is a crucial cytokine that is commonly released during infection, and excessive release of IL-6 can lead to the activation of the coagulation pathway, damage to the vascular endothelial cells, and inhibition of myocardial function [4]. In a meta-analysis of clinical trials for patients hospitalized with COVID-19, administration of the IL-6 receptor antibody tocilizumab was associated with lower 28-day all-cause mortality compared to usual care or placebo [5]. However, there is limited information available on the use of IL-6 targeting agents for cytokine storms induced by severe infections in patients with hematological malignancies. Here we present four cases of hematological malignancy patients who experienced significant elevation of IL-6 levels due to severe infection and were treated with tocilizumab. These results may serve as a reference for similar circumstances (Fig. 1).

Fig. 1.

The dynamic change of IL-6 and CRP concentration (↓ the beginning of the tocilizumab administration)

Methods

The study was conducted at Peking University First Hospital from November 2020 to January 2022. Four patients, ranging in age from 35 to 59, were admitted to the hospital. Three patients were diagnosed with acute leukemia and one patient was diagnosed with multiple myeloma. Severe infections and cytokine storms were identified for all four patients during the agranulocytosis phase, three before the white blood cells engraftment in the hematopoietic stem cell transplantation, and one after the introduction chemotherapy.

Along with antibiotics, all four patients received tocilizumab to alleviate the cytokine storm. In this small cohort of patients, tocilizumab was given when sepsis or septic shock was diagnosed according to the Sepsis-3[6] with serum level of IL-6 exceeds 1000 pg/ml. The patients’ clinical features, laboratory results, and specific treatment regimens were documented.

Results

Patient characteristics

Patient and disease characteristics are listed in Table 1. All four patients in our cohort underwent at least one cycle of chemotherapy, with patient no. 1 receiving seven cycles of chemotherapy and an autologous stem cell transplantation. Three patients experienced infections prior to chemotherapy and the duration of agranulocytosis ranged from 3 to 29 days before the onset of this infection episode.

Table 1.

Clinical characteristics of four patients

Patient	No. 1	No. 2	No. 3	No. 4
Age, y	51	35	59	52
Sex	Male	Male	Female	Male
Primary diagnosis	MM	AML	AL	AML
Previous treatment	IRD*3, ITD*3, PAD, ASCT; BEAM	IA, MD Ara-c	D + IA + VP	IA, MD Ara-c, D + VEN + HA
Previous infection	No	C.tropical	AB	CRKP
Duration of agranulocytosis	3 d	10 d	29 d	10 d
Infection sites	Gastrointestinal & bloodstream	Bloodstream	Bloodstream & perianal	Bloodstream
Proved pathogens	CREC	C.tropical	CRPA	CRKP
IL-6 (pg/ml)	19,246	1001.97	3187.0	5239.25
CRP (mg/l)	415.93	145.64	151.14	107.65
PCT (ng/ml)	39.9	1.29	4.17	1.24
Creatinine (umol/l)	123.76	119.19	119.4	108.4
Peak of IL-6 (pg/ml)	19,246	28,395.4	43,840.5	118,422
Infection complication	Septic shock	AF & HF AKI & decrease of muscle force	Septic shock II-RF	Paralytic intestinal obstruction AKI GI bleeding

MM multiple myeloma, IRD ixazomib + lenalidomide + dexamethasone, ITD ixazomib + thalidomide + dexamethasone, PAD bortezomib + liposome doxorubicin + examethasone, ASCT autologous stem cell transplantation, BEAM BCNU + etoposide + cytarabine + mephalon, CREC carbapenem-resistant Escherichia coli, AML acute myelogenous leukemia, IA idarubicin + cytarabine, MD Ara-C medium-dose cytarabine chemotherapy, C.tropical Candida tropicalis bloodstream infection, D + IA + VP decitabine + idarubicin + cytarabine + vindesine sulfate + prednisone, AB Acinetobacter baumannii, CRPA carbapenem-resistant Pseudomonas aeruginosa, D + VEN + HA decitabine + venetoclax + homoharringtonine + cytarabine, CRKP carbapenem-resistant Klebsiella pneumoniae, II-RF type II respiratory failure, AF atrial fibrillation, HF heart failure

Infection manifestations

All four documented infection episodes were from bloodstream, with two cases having combined gastrointestinal or perianal infections. The infectious pathogen of patient no. 2 was identified as Candida tropicalis by blood culture, which was resistant to voriconazole. The other three patients were infected with Gram-negative bacilli that were resistant to carbapenem.

Patient no. 1 was a 51-year-old male who developed neutropenia after the BEAM conditioning regimen for his auto-HSCT. He developed a fever which reached 39.0–41.0 °C on the fourth day post-transplantation. The patient also experienced chills, intermittent abdominal pain, and watery stool. Antibiotics were given to treat the fever, including imipenem (0.5 g every 6 h with the first dose of 1.0 g), and later tigecycline (16 h after the onset of fever due to the identification of Gram-negative bacilli that were probably resistant to carbapenem in the blood culture). Despite adequate fluid infusions and additional antibiotics, the patient’s fever persisted, till to 5 days after transplantation, accompanied by chills and hypotension. CRP and PCT surged significantly with increasing serum creatinine levels. The patient’s maximum serum IL-6 level reached 19,246 pg/ml. Despite the addition of norepinephrine and ceftazidime-avibactam, the patient’s blood pressure continued to drop and the laboratory results did not improve.

Patient no. 2 received a conditioning regimen of decitabine-Bu/Mel/Cy-ATG, followed by allogeneic hematopoietic stem cells from an unrelated matched donor. Two days after transplantation, the patient developed intermittent fever, severe swelling and pain in his right knee, ankle, and interdigital joints. Ipenem, linezolid, and voriconazole were administered, but his fever and joint pain did not improve. On day 8 post-transplantation, his blood culture revealed Candida tropicalis infection that was resistant to voriconazole. Then, micafungin combined with posaconazole was initiated (6 days after the onset of fever). However, the patient subsequently developed various conditions, including sinus tachycardia, atrial fibrillation, myocardial injury, renal injury, and decreased muscle force. A number of tests, including head MRI, lung CT, UCG, abdominal ultrasonography, and cerebrospinal fluid examination, were conducted to exclude potential infection sites, but no evidence of infection was found.

Patient no. 3 was diagnosed with acute leukemia of ambiguous lineage and received chemotherapy with decitabine + IA + VP. After chemotherapy, she developed agranulocytosis and intermittent fever. The peripheral blood metagenomic next-generation sequencing (mNGS) revealed Acinetobacter baumannii infection, and accordingly, mepine and tigecycline were used to treat her. Her temperature dropped to normal for 5 days. But then, her fever reached 39–40 °C again, accompanied by red, swollen, and gradually ulcerated perianal skin. As a result, polymyxin B was added to her treatment (17 h since onset of fever). However, the subsequent peripheral blood pathogen mNGS revealed Pseudomonas aeruginosa infection, and mepine was replaced by piperacillin sodium and tazobactam sodium (2 days after the onset of fever). Despite the change in treatment, the patient still had a persistent fever and suddenly lost consciousness 3 days later. Her heart rate increased, blood pressure decreased, and she experienced type II respiratory failure. To address her condition, she underwent endotracheal intubation and ventilator-assisted ventilation.

Patient 4 was diagnosed with refractory/relapsed acute myeloid leukemia and received allogeneic hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of D + Bu/Flu + ATG. He developed fever and diarrhea during conditioning regimen. Given the patient’s history of CRKP (carbapenem-resistant Klebsiella pneumoniae) and persistent agranulocytosis, colistin B was added immediately. Then, the patient’s temperature decreased to normal levels. However, 3 days later, the patient continued to have a high fever and increased levels of inflammatory markers. Additionally, the patient gradually developed paralytic intestinal obstruction, acute renal injury, and gastrointestinal bleeding.

Management and outcome of concomitant tocilizumab therapy

Patient no. 1 was given two doses of the tocilizumab (8 mg/kg), resulting in the stabilization of his blood pressure and discontinuation of norepinephrine. The patient’s temperature and inflammation markers began to decrease, with a drop in peak temperature and a decrease in PCT and CRP. On day + 6 post-transplantation, his blood culture revealed carbapenem-resistant E. coli infection, which was only sensitive to tigecycline and colistin, but resistant to other antibiotics including ceftazidime-avibactam. Therefore, ceftazidime-avibactam was replaced with colistin B treatment (52 h after onset of fever), and tocilizumab was continued. Eventually, the patient’s body temperature returned to normal, and the inflammatory markers decreased. The patient’s clinical status improved with the successful control of infection and hematopoietic implantation, and he was discharged.

Patient 2 received treatment with methylprednisolone and five doses of tocilizumab (8 mg/kg) based on his IL-6 level. With the decrease of inflammatory biomarkers, the patient achieved stable renal function 1 month post-transplantation, normal myocardial enzymes 3 months post-transplantation, and recovery of muscle strength to grade IV 6 months post-transplantation. The patient is alive with a complete remission from leukemia.

Patient 3 was infused with tocilizumab (8 mg/kg/day) and ceftazidime-avibactam to replacement of piperacillin sodium and tazobactam sodium (72 h after fever). Her level of consciousness gradually improved, the heart rate and blood pressure stabilized, and she was removed from ventilator-assisted ventilation 2 days later. Later, Pseudomonas aeruginosa was identified through the blood culture and was found sensitive to polymyxin B and ceftazidime-avibactam, intersensitive to iperacillin sodium and tazobactam sodium but resistant to mepine. There was a significant decrease in the patient’s CRP and PCT levels. In addition to intravenous antibiotics and perineal care, tocilizumab at a dose of 8 mg/kg/day infusion was continued. The patient’s body temperature gradually returned to normal and both renal and respiratory function stabilized. The patient achieved complete hematological remission and received sequential chemotherapy and allogeneic hematopoietic stem cell transplantation.

Patient 4 received tocilizumab (8 mg/kg/day) and cefoperazone-avebactam treatment immediately after the second onset of fever. However, multiple blood cultures revealed multiple-drug-resistant Klebsiella pneumonia, which was not sensitive to any of the antibiotics. The patient ultimately died from respiratory and circulatory failure.

Discussion

Febrile neutropenia is a common and serious complication in patients with hematological malignancies receiving chemotherapy or HSCT, and is associated with a high mortality rate. The increasing prevalence of infections caused by multidrug-resistant bacteria or fungi pose significant challenge in treating this high-risk patient population. Previous studies have demonstrated that overall 30-day mortality rate after CRE bacteremia in patients with hematologic malignancies ranges from 52 to 63%, and CRE-related mortality rates accounted for 51–54% [7, 8]. In regards to bloodstream infections, the reported 30-day mortality rate is approximately 24.2%, and patients with neutropenia and hematological malignancies have a 15–20% rate of poor clinical response to antifungal therapy [9, 10].

Infections are widely considered as the most common trigger for the cytokine storm. The immune response’s efforts to eliminate the pathogen can cause collateral damage that can be more fatal than the pathogen itself [11]. During the initial phase of a cytokine storm, various cytokines such as TNF-α, IL-1, IL-3, IL-6, IL-8, IFN-γ, MCP-1, and macrophage migration inhibitory factor are highly expressed [12]. Among these cytokines, IL-6, which is essential for both innate and adaptive immunity, is required for efficient pathogen clearance. Additionally, IL-6 has an important physiological role in humans, regulating the acute-phase response, hematopoiesis, metabolic rate, lipid homeostasis, and neural development. However, excessive production of IL-6 can lead to fever, cell death, coagulopathies, and eventually multiorgan dysfunction [13, 14].

Antibiotics play a vital role in treating infections that trigger cytokine storms. However, a severe cytokine storm can pose a significant challenge, especially for high-risk neutropenic patients, as it can be deadly before antibiotics agents take effect. Despite these high mortality rates, no effective immunotherapy has been developed to address this issue.

Experimental studies on cytokine targeting therapies, especially against TNF-α and IL-1, have shown promising results in sepsis models. However, clinical trials on TNF or IL-1 inhibitors failed to show beneficial outcomes for patients with sepsis [15, 16]. Additionally, several clinical trials aimed at targeting the coagulation cascade molecules such as TF and thrombin have also been unsuccessful to treat sepsis [17]. Targeting IL-6 may be promising to treat severe sepsis, septic shock, and noninfectious systemic inflammatory response syndrome (SIRS), as the complex IL-6/sIL-6R is implicated in inducing thrombosis, vascular leakage, and myocardial dysfunction, which can lead to multiple organ dysfunction and disseminated intravascular coagulation (DIC). In IL-6 gene knock-out mice, the complete deletion of IL-6 activity inhibits the development of multiple organ dysfunction in zymosan-induced acute peritoneal inflammation [18]. In acid aspiration-induced acute lung injury mice model, IL-6 knockout exhibits a significant improvement in lung function, edema formation, and decreased lung pathologies [19]. Furthermore, several studies have demonstrated that tocilizumab, a humanized monoclonal antibody targeting the IL-6 receptor, effectively reduces serum IL-6 levels and improves outcomes. Using rat models, Ibrahim et al. [20] demonstrated that tocilizumab could alleviated sepsis-induced acute lung injury (ALI) and kidney injury (AKI) with histological evidence, and increased survival rate in treated rats. In addition, a meta-analysis of clinical trials of patients hospitalized with COVID-19, administration of IL-6 antagonists was associated with lower 28-day all-cause mortality compared to usual care or placebo [5].

In our study, the first three patients developed resistant-drug bacterial or fungal infections during the myelosuppression period. The first patient showed an increase in the inflammatory biomarkers within 24 h of developing a fever, along with hypotension that required vasopressor support and elevated serum creatinine levels. Several improvements were observed in SIRS after 2 doses of tocilizumab were administered. The second patient was identified resistant to Candidemia and received micafinnet and posaconazole. Despite these treatments, multiple organ injuries were observed, including heart, kidney, and nerve-muscle injuries, and IL-6 levels continued to rise. Tocilizumab and methylprednisolone were administered, leading to decreased levels of CRP and improved organ functions without adjusting the anti-infection regimen. The third patient suffered from bloodstream and perianal infection and was given antibiotics. However, the patient developed consciousness disorders and respiratory failure, requiring mechanical ventilation. The levels of IL-6 and other inflammatory indicators were remarkably elevated. After administering tocilizumab and adjusting anti-infection treatment, the patient’s consciousness returned and was successfully removed from mechanical ventilation, avoiding multiple organ failures. The results suggest that, in the presence of effective anti-infection treatment, tocilizumab may help the recovery from an inflammatory state and prevent damage to multiple system functions caused by inflammatory factors. The fourth patient suffered from persistent agranulocytosis and a lack of sensitive antibiotics, and despite receiving tocilizumab, his condition could not be reversed.

It is important to note that tocilizumab is an IL-6 receptor antagonist, and administration may temporarily increase serum IL-6 levels. The efficacy of tocilizumab should be evaluated based on overall patient status, not just changes in IL-6 levels. Additionally, IL-6 has anti-inflammatory properties and plays a role in the host defense against infections. Thus, IL-6 inhibition may potentially exacerbate infections and delay recovery from sepsis [4]. Further studies and clinical experiences are needed to determine the appropriate population, dose, and timing of using IL-6 receptor antagonists.

In conclusion, we present four cases of cytokine storm induced by severe infection with hematologic malignancy. The use of tocilizumab as an adjuvant therapy showed promising results, warranting further investigation. The potential benefits of tocilizumab as a treatment for cytokine storm should be carefully balanced against its potential risks and the need for additional supportive therapies. The administration of IL-6 receptor antagonists should be closely monitored and evaluated in the context of a comprehensive patient care plan.

Author contribution

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Wang Bingjie, Wang Qian, Liang Zeyin, Yin Yue, Wang Lihong, and Wang Qingya. The first draft of the manuscript was written by Wang Bingjie and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Declarations

Ethics approval and consent to participate

The research complied with the Declaration of Helsinki and was approved by the ethics committee of Peking University First Hospital. Written informed consent was obtained from each participant.

Competing interests

The authors declare no competing interests.