Treatment patterns and survival outcomes of patients admitted to the intensive care unit due to immune‐related adverse events of immune checkpoint inhibitors

Abstract

Introduction
Severe immune‐related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center.

Methods
All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan–Meier method.

Results
Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti‐PD‐1 plus anti‐CTLA‐4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes‐related ketoacidosis (n = 8), immune‐related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2–6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0—NA).

Conclusion
The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long‐term survival.

Full text

Cancer Medicine. 2024;13:e7302.
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1 of 7
https://doi.org/10.1002/cam4.7302
wileyonlinelibrary.com/journal/cam4
Received: 12 October 2023
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Revised: 19 March 2024
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Accepted: 6 May 2024
DOI: 10.1002/cam4.7302
RESEARCH ARTICLE
Treatment patterns and survival outcomes of patients
admitted to the intensive care unit due to immune- related
adverse events of immune checkpoint inhibitors
LishiLin1
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Aletta P. I.Houwink2
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Jolanda M.vanDieren3
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Esther K.Wolthuis2
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Johannes V.vanThienen4
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Michiel S.vanderHeijden4
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John B. A. G.Haanen4,5,6
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Jos H.Beijnen1,7
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Alwin D. R.Huitema1,8,9
1Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
2Department of Anaesthesiology and Intensive Care, The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital, Amsterdam, The
Netherlands
3Department of Gastrointestinal Oncology, The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
4Department of Medical Oncology, The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
5Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital, Amsterdam,
The Netherlands
6Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
7Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
8Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
9Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.
Correspondence
Lishi Lin, Department of Pharmacy &
Pharmacology, The Netherlands Cancer
Institute—Antoni van Leeuwenhoek
Hospital, Plesmanlaan 121, 1066 CX
Amsterdam, The Netherlands.
Email: l.lin@nki.nl
Abstract
Introduction: Severe immune- related adverse events (irAEs) due to immune
checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU).
In this retrospective study, we determined the incidence, treatment patterns and
survival outcomes of this patient population at a comprehensive cancer center.
Methods: All patients admitted to the ICU due to irAEs from ICI treatment
between January 2015 and July 2022 were included. Descriptive statistics were
reported on patient characteristics and treatment patterns during hospital admis-
sion. Overall survival (OS) from the time of ICU discharge to death was estimated
using the Kaplan–Meier method.
Results: Over the study period, 5561 patients received at least one ICI admin-
istration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs.
Twenty patients were treated with anti- PD- 1 plus anti- CTLA- 4 treatment,
whereas 12 patients were treated with ICI monotherapy. The type of irAEs were
de novo diabetes- related ketoacidosis (n = 8), immune- related gastrointestinal
toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis
(n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days

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1
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INTRODUCTION
Ipilimumab was the first immune checkpoint inhibitor
(ICI) receiving drug approval in 2011 for the treatment
of metastatic melanoma.1 Since then, multiple ICIs have
been approved for a variety of advanced cancer types, and
this number will likely continue to increase in the future.2
These ICIs have revolutionized the field of cancer treat-
ment, and ICI treatment is shifting from later- line treat-
ment options to earlier disease settings.3 In addition, ICI
are gaining ground as adjuvant and neoadjuvant treat-
ment options in early- stage cancer.4–8
It is estimated that one third of patients with cancer
is eligible for ICI treatment based on data from the US,
whereas with the ongoing developments the number of
patients who will receive ICI treatment in future will
likely increase.9 As a consequence, the number of patients
experiencing adverse events will also increase.10 A unique
type of adverse event associated with the use of ICIs is the
class of immune- related adverse events (irAEs). These
irAEs are autoimmune conditions that can affect any or-
gansystem in the body.11
The European Society of Medical Oncology released
a clinical practice guideline on the management of
ICI- induced irAEs, in which corticosteroids are recom-
mended as first- line treatment, followed by other im-
munosuppressive therapies depending on the severity
of the irAEs and organ systems involved.12 In severe
cases, hospitalization is required to treat irAEs, whereas
intensive care unit (ICU) admissions can be required to
monitor and support organ functions in life- threatening
situations.
Only a limited number of studies have been conducted
to specifically determine the treatment course and sur-
vival outcome of patients hospitalized due to irAEs, which
is especially true for patients admitted to the ICU.13–16
Therefore, this retrospective study aimed to determine the
incidence, treatment patterns, and survival outcomes of
patients administered to the ICU of a comprehensive can-
cer center as a result of ICI- induced toxicity.
2
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METHODS
This retrospective study was performed at the Netherlands
Cancer Institute—Antoni van Leeuwenhoek Hospital
(NKI- AvL), Amsterdam, the Netherlands, which is a
comprehensive cancer center. The ICU of the NKI- AvL is
classified as a level 2 ICU according to the report of the task
force of the World Federation of Societies of Intensive and
Critical Care Medicine.17 Our ICU is an eight bed facility,
which is the only monitoring facility in our hospital since
there is no cardiac care unit or emergency department.
The total number of patients who received at least one
administration of atezolizumab, avelumab, cemiplimab,
dostarlimab, durvalumab, ipilimumab, nivolumab, or
pembrolizumab at our institute between January 2015
and July 2022 was determined. Patients aged 18 years or
older were included in this study if they were admitted to
the ICU due to irAEs of ICIs. Patients who did not con-
sent to their data being used for research were excluded.
No other exclusion criteria were applied. The assessment
whether ICU admittance was due to irAEs was performed
by the treating physician and reviewed by investigators
(LL and AHo). In case a patient experienced more than
one type of irAE, distinction was made between the irAE
contributing most to ICU admission and additional irAE.
Gastrointestinal irAEs were confirmed by biopsies as part
of the standard of care. Other types of irAEs, such as ne-
phritis, were not confirmed by biopsies as part of the stan-
dard of care.
In case of gastrointestinal irAE and nephritis, biopsies
were conducted to confirm the irAEs.
For all patients admitted to the ICU, type of malig-
nancy, data on ICI treatment, irAE treatment, ICU ad-
mission, sequential organ failure assessment (SOFA)
score, and survival outcomes were collected. The SOFA
score is used to assess the severity of organ dysfunction
in critically ill patients at the ICU, which is also used
as a predictor for mortality based on six organ systems.
SOFA scores range from 0 to 24 with higher scores in-
dicating a worse prognosis.18 Overall survival (OS) was
(interquartile range: 2–6 days). Three patients died during ICU admission. The
median OS of the patients who were discharged from the ICU was 18 months
(95% confidence interval, 5.0—NA).
Conclusion: The incidence of irAEs leading to ICU admission in patients treated
with ICI was low in this study. ICU mortality due to irAEs was low and a subset
of this patient population even had long- term survival.
KEYWORDS
immune checkpoint inhibitors, immune- related adverse events, intensive care unit, survival

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defined as the time from ICU discharge to death by
any cause and follow- up data was collected until July
2023. Data were extracted from the electronic medical
records Hix (Chipsoft, Amsterdam, the Netherlands)
and Metavision (iMDsoft, Dedham, Massachusetts, The
United States). The conduct of this observational study
was approved by the Investigational Review Board of
the NKI- AvL and the need for written informed consent
was waived.
For quantitative data, results were expressed as me-
dians with interquartile ranges. For categorical data, fre-
quencies and percentages were used. OS was estimated
using the Kaplan–Meier method and the median OS in-
cluding the 95% confidence interval (CI) was reported.
Statistics were performed in R version 4.2.1. (R Foundation
for Statistical Computing, Vienna, Austria).
3
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RESULTS
Over the study period, 5561 patients received at least one
ICI administration at our institute, of which 32 patients
(0.6%) were admitted to the ICU due to irAEs. The
characteristics of this patient population are depicted in
Table1. Twenty patients (63%) were treated with anti-
PD- 1 plus anti- CTLA- 4 treatment, whereas 12 patients
(37%) were either treated with anti- CTLA4 or anti- PD- 1/
PD- L1 monotherapy. The median duration of ICU stay
was 3 days. The median SOFA score on the first day of ICU
stay was three.
The observed irAEs were de novo diabetes- related ke-
toacidosis (n = 8), immune- related (IR) gastrointestinal
toxicity (n = 8), myocarditis or myositis (n = 10), nephri-
tis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The
duration from the first ICI administration until hospital-
ization due to irAEs varied between patients. Noteworthy,
most patients with myocarditis, myositis, and nephritis
developed irAEs after one or two ICI administrations. In
addition to the irAE contributing most to ICU admission,
some patients experienced multiple types of irAEs. For
example, three patients with diabetes- related ketoacidosis
also experienced IR- gastrointestinal toxicity or hepatitis.
In addition, a distinction between myocarditis and myo-
sitis as the main irAE contributing to ICU admission was
not always clear.
The treatment of these irAEs for each patient is de-
picted in Figure1. The eight patients with de novo
diabetes- related ketoacidosis received treatment with in-
sulin, of which three also received immunosuppressive
therapy. In total, twenty seven patients (84%) received
treatment with corticosteroids. In addition to corticoste-
roid treatment, eight patients (25%) received treatment
with infliximab, which was mostly given in patients with
TABLE  Characteristics of patients admitted to the intensive
care unit (ICU) due to immune- related adverse events (irAE) of
immune checkpoint inhibitors (ICIs).
Patients N = 32 (%)
Age, years
Median (IQR) 66 (58–72)
Male sex 26 (81)
ECOG PS at time of start treatment
0 17 (53)
1 12 (38)
NA 3 (9)
ICI used
Atezolizumab 1 (3)
Durvalumab 1 (3)
Ipilimumab 3 (9)
Nivolumab 4 (13)
Nivolumab + ipilimumab 20 (63)
Pembrolizumab 3 (9)
Type of cancer
Melanoma 17 (53)
Lung 5 (16)
Urothelial 3 (9)
Renal 2 (6)
Colorectal 2 (6)
Mesothelioma 2 (6)
Breast 1 (3)
Type of irAE
Gastrointestinal 8 (25)
Ketoacidosis 8 (25)
Myocarditis and myositis 4 (13)
Myocarditis 4 (13)
Myositis 2 (6)
Nephritis 3 (9)
Pneumonitis 2 (6)
Myelitis 1 (3)
Time from ICI initiation until hospital admission due to irAE
(days)
Median (IQR) 44 (29–205)
Duration of hospital admission (days)
Median (IQR) 15 (7–24)
Duration of ICU admission (days)
Median (IQR) 3 (2–6)
SOFA score, day 1
Median (IQR) 3 (1–5)
SOFA score, highest during ICU stay
Median (IQR) 4 (2–6)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance
status; IQR, interquartile range; SOFA, sequential organ failure assessment.

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IR- gastrointestinal toxicity. Treatment with tacrolimus
was administered in six patients (19%) and treatment with
mycophenolate mofetil was administered in six patients
(19%). In eight cases, patients were already started on
corticosteroid treatment and other immunosuppressive
treatment before hospital admission. In addition, seven
patients (22%) required mechanical ventilation at the ICU,
whereas two patients (6%) received renal replacement
therapy and two patients (6%) received plasmapheresis.
Three patients (9%) died during ICU admission.
One patient died due to haemorrhagic shock caused by
large duodenal ulcers. The second patient died due to a
myocarditis- related irreversible cardiogenic shock. The
third patient decided to cease all treatment as a long re-
covery would be needed due to a combination of my-
ositis and myocarditis, whereas no options remained
to treat the underlying disease (mesothelioma). These
three patients received only one or two cycles of anti-
PD- 1 plus anti- CTLA- 4 treatment. Median OS of patients
discharged from the ICU was 18 months (95% CI, 5.0—
NA) (Figure2A). Median OS of this patient population
excluding patients with de novo diabetes- related keto-
acidosis was 6.3 months (95% CI, 2.2—NA) (Figure2B).
No patients died on the general wards after ICU dis-
charge, whereas six patients (19%) died within a month
after hospital discharge. These patients had a poor prog-
nosis, which was often due to a combination of the irAE
and disease progression. An additional six patients (19%)
died within 6 months after hospital discharge.
Four patients (13%) were readmitted within 30 days
of discharge. In three of these patients, the readmission
was related to the irAEs, whereas during hospital read-
mission additional immunosuppressiive treatment was
administered. The other readmitted patient developed an
FIGURE  Overview of treatment course of patients administered to the intensive care unit (ICU) due to immune- related adverse
events of immune checkpoint inhibitors (ICIs) in days. One row represents one patient: the x- axis shows time in days in which the black
arrow indicates that the current ICI treatment was initiated longer ago. Previous and current ICI: type of ICI administered including
the number of administrations. Atezolizumab (A), durvalumab (DU), ipilimumab (I), nivolumab (N), nivolumab + ipilimumab (NI),
pembrolizumab (P). SOFA: SOFA score in the first 24 h of ICU stay (SOFA 24) and highest score during (first) ICU stay (SOFA H). SP:
support in the form of mechanical ventilation (V), renal replacement therapy (R), and plasmapheresis (F). FU: follow- up information
including death during ICU stay (D), readmission (RA), and rechallenge with ICI (RC). OS: overall survival of patients discharged from the
ICU in months with ‘+’ indicating that the patient was censored.

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infection, which was possibly related to the immunosup-
pressive treatment.
There were five patients (16%) who received a different
ICI prior to the ICI treatment on which they developed
irAEs. In all cases, no signs of irAEs were observed during
the first ICI treatment line. Additionally, five patients (16%)
were rechallenged with ICI treatment after ICU admission.
Three patients were rechallenged with anti- PD- 1 treatment
and no recurrent irAEs were observed, whereas two pa-
tients were rechallenged with anti- CTLA- 4 monotherapy or
combination therapy, who did experience recurrent irAEs.
These two patients initially presented with de novo diabetes-
related ketoacidosis, whereas during the rechallenge they
presented with immune- related hypophysitis and hepatitis.
Both patients were treated with prednisolone.
4
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DISCUSSION
This retrospective study determined the characteristics,
treatment patterns and survival outcomes of patients
admitted to the ICU due to irAEs from ICIs. The incidence
of irAEs leading to ICU admission in patients treated with
ICIs was low (0.6%), whereas ICU mortality was limited.
The frequency of irAEs leading to ICU admission in
our study was much lower than the incidence of grade 3 or
higher irAEs reported in the literature.12,19 Especially the
frequency of IR- gastrointestinal toxicity leading to ICU
admission was low compared to the incidence of grade 3
or higher colitis that occurs in 1–9% of patients depending
on whether ICI monotherapy or combination therapy was
given.19 Good awareness of irAEs, instructing patients to
call at the first signs of a suspected IR- gastrointestinal tox-
icity and immediate treatment initiation with corticoste-
roids may, therefore, prevent the worsening of irAEs and
therefore also ICU admissions.
Consistent with the literature, anti- CTLA- 4 treatment
with or without anti- PD- 1 treatment is associated with a
higher risk of the development of irAEs leading to ICU
admission compared to anti- PD- 1/PD- L1 monotherapy in
our study.12 This higher risk to develop irAEs was also ob-
served in our study within individuals who were treated
with multiple ICI treatments. Patients who received anti-
PD- 1/PD- L1 treatment prior to anti- CTLA- 4 treatment
with or without anti- PD- 1 treatment, did not develop
irAEs on the prior ICI treatment. In addition, patients
who were rechallenged with anti- PD- 1/PD- L1 monother-
apy did not develop irAEs, whereas patients rechallenged
with anti- CTLA- 4 treatment with or without anti- PD- 1
treatment, did develop irAEs.
Regarding the onset of different types of irAEs,
immune- related myocarditis, myositis, and nephritis had
a fast onset after ICI initiation. This fast onset was also
observed for myositis in a study by Touat etal., in which
the median onset was 25 days.20 For nephritis; however,
different studies reported means or medians varying from
3 till 9 months after ICI initiation.21
In two other studies investigating ICU admission due
to irAEs from ICI treatment, pulmonary irAEs were most
common, which were respectively 28% and 64% of irAEs
leading to ICU admission.13,16 This differed from our re-
sults in which de novo diabetes- related ketoacidosis and
IR- gastrointestinal toxicity were observed most frequently.
A potential explanation for the high incidence of de novo
diabetes- related ketoacidosis may be due to a different
treatment policy for de novo diabetes- related ketoacidosis
between the hospitals, as other hospitals may treat keto-
acidosis at the general ward instead of the ICU. The ICU
mortality in our study was lower compared to these two
studies, which were 17% and 22%, respectively, whereas
the SOFA score on the first day of ICU admittance was
similar between our study and the study of Joseph etal. In
addition, OS of patients admitted to the ICU due to irAEs
was similar compared to the study of Joseph etal., which
FIGURE  Overall survival (OS) of (A) patients from the time
of intensive care unit (ICU) discharge till death and (B) patients
without de novo diabetes- related ketoacidosis. CI, confidence
interval; NA, not available.

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seemed to be longer compared to ICU admittance due to
other reasons such as disease progression.13
There are several limitations in our study, which are
inherent to the retrospective nature of this study and the
low number of patients admitted to the ICU due to irAEs.
Due to the low number of patients, it was not possible to
compare the survival of patients with different types of
irAEs. However, one can imagine that patients with de
novo diabetes- related ketoacidosis will have a better prog-
nosis compared to other irAEs that need to be managed
with immunosuppressive treatment. Therefore, addi-
tional studies are needed to study the survival outcomes
between different types of irAEs. In addition, the fraction
of patients needing ICU admission due to irAEs may be
slightly underestimated, due to the possibility of ICU ad-
mittance at another hospital or a loss to follow- up.
In conclusion, the incidence of irAEs leading to ICU
admission in patients treated with ICIs was low in this
study. ICU mortality due to irAEs was low and a subset
of this patient population even had long- term survival.
Therefore, awareness of irAEs among all physicians in-
volved in immunotherapy treatment, immediate initiation
of corticosteroid treatment upon suspicion of irAEs and
continuous multidisciplinary communication between
the critical care and the oncology team is essential for the
optimal treatment of this patient population.
AUTHOR CONTRIBUTIONS
Lishi Lin: Conceptualization (equal); data curation (lead);
formal analysis (lead); methodology (equal); writing – orig-
inal draft (lead). Aletta P. I. Houwink: Conceptualization
(equal); data curation (supporting); formal analysis (sup-
porting); methodology (equal); writing – review and ed-
iting (equal). Jolanda M. van Dieren: Data curation
(supporting); formal analysis (supporting); writing – re-
view and editing (equal). Esther K. Wolthuis: Writing
– review and editing (equal). Johannes V. van Thienen:
Writing – review and editing (equal). Michiel S. van der
Heijden: Writing – review and editing (equal). John B. A.
G. Haanen: Writing – review and editing (equal). Jos H.
Beijnen: Supervision (supporting); writing – review and
editing (equal). Alwin D. R. Huitema: Conceptualization
(equal); methodology (equal); supervision (lead); writing –
review and editing (equal).
CONFLICT OF INTEREST STATEMENT
L. Lin, A.P.I. Houwink, J.M. van Dieren, E.K. Wolthuis,
J.V. van Thienen and A.D.R. Huitema declare no conflict
of interest. M.S. van der Heijden has received research
grants (paid to the institute) from BMS, AstraZeneca,
Roche and 4SC and has served as an advisor (fees paid
to the institute) to Roche, Pfizer, Astellas, Astra Zeneca,
Merck Sharp and Dome, BMS, and Janssen. J.B.A.G.
Haanen reports an advisory role for AZ, Achilles
Therapeutics, BioNTech, Bristol- Myers Squibb, CureVac,
Imcyse, Immunocore, Instil Bio, Iovance Biotherapeutics,
Ipsen, Molecular Partners, MSD Oncology, Neogene
Therapeutics, Novartis, PokeAcell, Roche/Genentech,
Sanofi, Scenic, Third Rock Ventures and T- Knife; has
received research funding (paid to the institute) from
Amgen, Asher Biotherapeutics, BioNTech, Bristol- Myers
Squibb, MSD, Neon Therapeutics, Novartis, Sastra Cell
Therapy; and is stock owner of Neogene Therapeutics. J.H.
Beijnen is a part- time employee and (indirect) shareholder
of Modra Pharmaceuticals BV. He is (partly) patent holder
of oral taxane formulations which are clinically developed
by Modra Pharmaceuticals BV (a spin- off company of the
Netherlands Cancer Institute), not related to this work.
DATA AVAILABILITY STATEMENT
The data generated and analyzed during the current study
are available from the corresponding author on reasonable
request.
ETHICS STATEMENT
Institutional Review Board of the Netherlands Cancer
Institute—Antoni van Leeuwenhoek.
ORCID
Lishi Lin https://orcid.org/0000-0002-9733-7720
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How to cite this article: Lin L, Houwink API,
van Dieren JM, et al. Treatment patterns and
survival outcomes of patients admitted to the
intensive care unit due to immune- related adverse
events of immune checkpoint inhibitors. Cancer
Med. 2024;13:e7302. doi:10.1002/cam4.7302