Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

Background Immune checkpoint inhibitors have reshaped the standard of care in oncology. However, they have been associated with potentially life-threatening immune-related adverse events. With the growing indications of immune checkpoint inhibitors and their position as a pillar of cancer treatment, intensive care physicians will be increasingly confronted with their side effects. The outcome of patients with severe immune-related adverse events in the intensive care unit remains unknown. This retrospective multicentric study aims to describe the characteristics of patients admitted to the intensive care units of 4 academic hospitals in Paris area while receiving immune checkpoint inhibitor treatment between January 2013 and October 2019. Results Over the study period, 112 cancer patients who received immune checkpoint inhibitors were admitted to the intensive care unit within 60 days after the last dose. ICU admission was related to immune-related adverse events (n = 29, 26%), other intercurrent events (n = 39, 35%), or complications related to tumor progression (n = 44, 39%). Immune-related adverse events were pneumonitis (n = 8), colitis (n = 4), myocarditis (n = 3), metabolic disorders related to diabetes (n = 3), hypophysitis (n = 2), nephritis (n = 2), meningitis or encephalitis (n = 2), hepatitis (n = 2), anaphylaxis (n = 2) and pericarditis (n = 1). Primary tumors were mostly melanomas (n = 14, 48%), non-small-cell lung cancers (n = 7, 24%), and urothelial carcinomas (n = 5, 17%). Diagnosis of melanoma and a neutrophil/lymphocyte ratio < 10 were associated with immune-related diagnosis versus other reasons for ICU admission. During their ICU stay, immune-related adverse events patients needed vasopressors (n = 7), mechanical ventilation (n = 6), and extra-corporeal membrane oxygenation (n = 2). One-year survival was significantly higher for patients admitted for irAE compared to patients admitted for other reasons (p = 0.004). Conclusions Admission to the intensive care unit related to immune-related adverse event was associated with better outcome in cancer patients treated with immune checkpoint inhibitors. Our results support the admission for an intensive care unit trial for patients with suspected immune-related adverse events.


Background
Immune checkpoint inhibitors (ICI) have revolutionized cancer care and have led to a significant survival improvement in a large variety of tumors [1].
The best standard of care for irAEs has not been established through randomized trials and research on the subject is considered an urgent need [6], but guidelines based on experts' opinion often place steroids as a firstline therapy [20,21], followed by other immunosuppressive therapies according to the type of irAE and the organ involved [22][23][24][25].
With the growing indications of ICI and their position as a pillar of cancer treatment, intensive care physicians will be increasingly confronted with their side effects.
The outcome of patients admitted to the ICU for irAEs remains unknown and may potentially differ from other oncological complications of patients admitted to the ICU [26].
This study aims to describe the characteristics of cancer patients receiving ICI and admitted to the ICU. Patients admitted for irAE were compared to patients admitted for other reasons.

Methods
We conducted a retrospective multicentric study including patients from 4 French university hospitals in Paris area. All centers were oncologic centers and were organized with a multidisciplinary board [27] to discuss the management of immune-related adverse events. Patients eligible were admitted to ICUs between January 2013 and October 2019, during the course of an ICI treatment (either anti-PD-1 (NIVOLUMAB, PEMBROLIZUMAB or SPARTALIZUMAB), anti-PDL-1 (ATEZOLIZUMAB, DURVALUMAB), anti-CTLA4 (IPILIMUMAB or TREMELIMUMAB) or a combination of ICI.
All consecutive adult patients admitted to the ICU who were receiving an ICI treatment for solid or hematological malignancy were included in the study. Patients admitted for less than 24 h in the ICU or patients who had stopped ICI treatment for more than 60 days before admission were not included. Investigational immunotherapies relying on inhibition of other checkpoints or mechanisms other than immune checkpoint inhibition and non-systemically administered immunotherapies were excluded.
All data were extracted from medical charts. Followup until 1 year after ICU admission was recorded.
Patients were then classified according to the reason for admission, whether related to an immune-related adverse event (irAE), an intercurrent adverse event not related to immunotherapy (intE) or a complication related to tumor progression (TumProg). Imputability of the ICI for irAEs was assessed by the physician in charge, discussed in multidisciplinary boards in most cases [27] and reviewed by investigators (AJ and VL), according to the World Health Organization Uppsala Monitoring Centre scale for standardized case causality assessment and organ-specific guidelines when available [16]. Tumor progression was defined as peritumoral hemorrhage, tumor obstruction or lymphangitis carcinomatosis. Intercurrent event was defined as any other medical condition neither related to tumor progression nor irAE. In case of concomitant tumor progression and immune-related or intercurrent event, the patient was classified a posteriori according to the reason for ICU admission as assessed by the physician in charge and reviewed by investigators (AJ and VL).

Statistical analysis
Results were expressed as median and 25th and 75th quartiles [Q1-Q3] for quantitative data and numbers and percentages for categorical data. Quantitative variables were compared using the Wilcoxon test, and qualitative variables were compared using the Chisquare test with Yate's continuity correction if needed. Baseline demographical, oncological, clinical and biological characteristics at ICU admission were described in the first table and relevant variables were tested for their association with irAE diagnosis (Fisher's test) and 1-year mortality (logistic regression). A multivariate logistic regression model included variables that were significantly associated with 1-year mortality in univariate logistic regression and clinically relevant variables. Kaplan-Meier curves until 1 year after ICU admission were stratified using significant variables and compared using log-rank tests. Follow-up of patients after discharge from the ICU until death or end of followup was represented in a swimmer plot, where different colors represent different types of irAEs. Reintroduction of an ICI and complete responses according to iRECIST [28] were depicted by pictograms. All statistical tests were two-sided with an α level of 0.05. Statistics were managed using R software version 3.4.2 (R Foundation for Statistical Computing, Vienna, Austria; https ://www.R-proje ct.org/).

Results
Between January 2013 and October 2019, 5644 cancer patients were admitted to the ICU and 112 of them (2%) were admitted within 60 days after an administration of ICI. Among them, 29 (26%) patients were admitted for an irAE, 44 (39%) patients were admitted for a complication related to tumor progression (TumProg) and 39 (35%) patients had another reason for ICU admission (intE) (Additional file 1: Figure S1).
The absolute number of patients admitted within the course of an immunotherapy showed a significant increase from 2013 to 2018 (Mann-Kendall test p = 0.024), whereas the proportion of irAEs within these years remained stable (Chi-squared test for trend p = 0.298) (Fig. 1).
All patients with pneumonitis, one patient with pericarditis and one patient with infusion-related hypersensitivity reaction were admitted for acute respiratory failures. The three patients with myocarditis, one patient with infusion-related hypersensitivity reaction and one patient with colitis were admitted for hemodynamic failure. The two patients with hepatitis were admitted for hepatic failure. All patients with diabetes and hypophysitis were admitted for hydroelectrolytic disorders. Meningitis and encephalitis patients were admitted for neurologic failure. Two patients with nephritis and two patients with colitis were admitted for acute kidney injury, whereas the last colitis patient was admitted for hemorrhage requiring emergency endoscopic evaluation.
The clinical characteristics and underlying disease of irAE patients at ICU admission are described in Table 1.
Ten out of 24 (41.7%) irAE patients died before one year after ICU admission.
As described in the swimmer plot (Fig. 2), patients died within the ICU course (n = 5/29, 17.2%) or quickly after discharge (n = 3/29, 10.3%). No death was registered more than 3 months after ICU discharge and one lymphoma patient was still alive 5 years after an ICI-induced pneumonitis that required non-invasive ventilation in the ICU.
Durations of treatment before ICU admission were not different between the groups.
The proportion of patients who stopped ICI treatment after ICU discharge was not different between the groups
Factors associated with one-year mortality in multivariate analysis (  Intensivists need to be aware of these new treatments leading to high survival rates with a good quality of life, even in patients with advanced cancer [1]. These treatments, leading to an increased immune response, have been associated with several immune-related disorders [29], most of which remain low grade and can be easily managed. However, toxicity-related mortality under ICI can reach 0.36% for anti-PD1 and 1.23% for anti-PD1/ anti-CTLA4 combination [30]. With an increased number of treated patients, number of fatal irAEs reported has increased more than threefold between 2015 and 2017 [30]. Therefore, intensivists should be aware of such severe complications with potential good outcomes after early diagnosis and treatment. Indeed, other complications may be easily ruled out with a simple diagnostic strategy relying on a close collaboration between oncologists and intensivists. Then immunosuppressive treatment including steroids should be quickly prescribed to reverse irAE [20,31,32] Systemic steroids are recommended for grade 3 and 4 immune-related adverse events [20,21,32,33]. For steroid-refractory irAEs, a personalized management based on the predominant immune infiltrate is advised [22,23]. However, there are not yet recommendations for salvage therapy when steroids fail to decrease toxicity. Thus, a close collaboration between oncologists and intensivists must be of importance. Based on treatment approaches for primary autoimmune disorders, early treatment by anti-TNFα in colitis [24,34] and plasma exchange in neurological toxicities [25] have been advocated.
The second result of importance of the study is the kind of admitted patients. Although ICI are usually prescribed for metastatic disease within first-or second-line treatment, patients may keep high performance status. Such patients could benefit from ICU admission. Moreover, in this study as in previous ones, ICI could be safely readministered and could lead to long-term responses [35,36]. Also, some patients with highly severe AE and in whom ICI was stopped have shown long-term response or stability. Immune-related adverse events have been shown to correlate with response rate, and some studies describe a better prognosis in patients experiencing irAEs [37][38][39]. Therefore, such adverse events do not lead to palliative treatment. However, performance status should be evaluated before ICU admission as it has been consistently associated with mortality in intensive care cancer patients [40].

Table 2 Factors associated with 12-month mortality in univariate and multivariate analysis in patients admitted in the intensive care unit (ICU) within 60 days after last dose of immune checkpoint inhibitor (ICI)
Hazard ratios and their 95% confidence interval are shown for factors associated with 12-month mortality in univariate and multivariate analyses OR for mortality ( Also, this study describes the clinical heterogeneity of such patients in the context of intensive care; the 3 most frequent diagnoses (pneumonitis, colitis and cardiac disorders) representing only approximately half of the patients. These adverse events have been already described [2]. Particularly, colitis has been associated with anti-CTLA4, whereas pneumonitis has been related to anti-PD1 treatment [41], as shown in our study. Moreover, we confirm the risk of severe AE when ICI combinations are used [2,30,42]. If our small sample size does not allow us to compare mortality across the different types of irAEs, larger cohorts from outside of the ICU have described high mortality rates [30] in myocarditis [16][17][18][19], pneumonitis [4][5][6] and hepatitis [11][12][13] patients. Although rarely lethal, colitis has been reported as the first cause of treatment-related death in patients under anti-CTLA4 therapy [30].
Some irAEs, such as diabetic ketoacidosis or acute hypophysitis, carry a good prognosis compared with more frequent conditions leading to ICU admissions in oncological patients. Such diagnoses should be easily raised and managed by intensivists even in patients with advanced cancer. Moreover, such irAEs can be managed without immunosuppressive treatment [36]. In our cohort, patients admitted for diabetes ketoacidosis and several other immune-related events did not receive steroids, highlighting the need for raising awareness of this kind of complication and establishing multidisciplinary protocols for the treatment of these patients, especially the ones who are critically ill.
There are several limitations in this study. First, this was a retrospective study including only patients admitted to the ICU. Although irAEs are rare, this study could include 112 patients treated with ICI and 29 irAEs. Compared to case reports, this is the largest study describing irAEs in the ICU setting. Moreover, comparison with other reasons of ICU admission in patients receiving ICI could be performed.
In such retrospective studies, admission bias remains the most important limitation. Indeed, most patients in our study had a high performance status that may not reflect all cancer patients, preventing a direct comparison to patients treated with conventional chemotherapies admitted in the ICU. However patients admitted to the ICU for non-immune-related reasons while receiving a treatment by an ICI have been compared to patients admitted for irAEs.
Third, we chose a timeframe of 60 days from the last dose to admission in the ICU. If time from first dose to onset of irAE has been deeply studied and varies largely among irAEs [2], time from last dose to irAE has been seldom reported. On the one hand, some irAEs have been reported up to 2 years after ICI cessation [43]. On the other hand, time from last dose to irAE does not seem to vary much between early and late-occurring irAEs, with a median time of 2 weeks in both colitis [44] and nephritis [45], similar to our findings. Thus, our 2-month timeframe between last ICI dose and admission in the ICU unlikely resulted in a significant admission bias, whereas it prevented issues concerning imputability of the ICI or comparability between the irAE group and patients admitted for non-immune-related reasons long after cessation of ICI.
Lastly, irAEs were heterogeneous and no risk factor could be determined for each type of irAE. However, the aim of our study was to increase knowledge of this kind of adverse events for intensivists. In the future, with the increasing number of ICI-treated patients, new combinations and probably higher risk of ICU admission, adverse events will be better evaluated [46].

Conclusions
In conclusion, intensivists should be aware of irAEs even in patients with advanced cancer. Such adverse events, with early diagnosis and treatment, may be associated with good outcomes even in the case of severe organ failure and in metastatic settings. These results justify ICU admission for such patients, but a close collaboration between oncologists and intensivists for diagnostic procedure and immunosuppressive treatment remains essential.