ArticlePDF Available

Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group

Authors:

Abstract and Figures

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs’ therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy. Electronic supplementary material The online version of this article (10.1186/s40425-017-0300-z) contains supplementary material, which is available to authorized users.
Content may be subject to copyright.
P O S I T I O N A R T I C L E A N D G U I D E L I N E S Open Access
Managing toxicities associated with
immune checkpoint inhibitors: consensus
recommendations from the Society for
Immunotherapy of Cancer (SITC) Toxicity
Management Working Group
I. Puzanov
1
, A. Diab
2
, K. Abdallah
3
, C. O. Bingham III
4
, C. Brogdon
5
, R. Dadu
2
, L. Hamad
1
, S. Kim
2
, M. E. Lacouture
6
,
N. R. LeBoeuf
7
, D. Lenihan
8
, C. Onofrei
9
, V. Shannon
2
, R. Sharma
1
, A. W. Silk
12
, D. Skondra
10
, M. E. Suarez-Almazor
2
,
Y. Wang
2
, K. Wiley
11
, H. L. Kaufman
12
, M. S. Ernstoff
1*
and on behalf of the Society for Immunotherapy of Cancer
Toxicity Management Working Group
Abstract
Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based
therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a
discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic
mechanisms responsible for the drugstherapeutic effects, namely blockade of inhibitory mechanisms that suppress
the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut,
endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal,
neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in
severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related
deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and
prolonged duration compared to adverse events from chemotherapy, and effective management depends on early
recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an
urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and
manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society
for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met
for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their
consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.
Keywords: Immune-related adverse events, Toxicity, Immune checkpoint inhibitor
* Correspondence: Marc.Ernstoff@RoswellPark.org
Equal contributors
1
Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95
DOI 10.1186/s40425-017-0300-z
Background
Cancer immunotherapy has revolutionized the treatment
of cancer [1, 2]. Currently, the most widely used ap-
proach is the administration of targeted monoclonal
antibodies (mAbs) directed against regulatory immune
checkpoint molecules that inhibit T cell activation [1].
At present, six immune checkpoint inhibitors (ICIs) are
approved by the U.S Food and Drug Administration
(FDA) for use in a variety of solid tumors, and one
hematological malignancy (Hodgkin lymphoma) [3]. Ipi-
limumab, a fully human IgG1 mAb that blocks the cyto-
toxic T lymphocyte-antigen-4 (CTLA-4), a checkpoint
inhibitor of T cell activation, was the first ICI approved,
in 2011, for use in advanced melanoma [4]. Pembrolizu-
mab and nivolumab, both engineered IgG4 mAbs that
regulate T cell activation by blocking the protein pro-
grammed death 1 (PD-1), received FDA approval in pa-
tients with advanced melanoma in 2014 [5, 6] and the
indications for both have subsequently expanded consid-
erably. Indeed, in a landmark regulatory step, the FDA re-
cently approved both pembrolizumab and nivolumab for
use in certain patients with mismatch repair deficient
(dMMR) and microsatellite instability high (MSI-H)
cancers that have progressed following treatment with
chemotherapy the first such tissue-agnostic,biomarker-
driven approvals granted [5, 6]. Both anti-PD-1 agents
are associated with negligible antibody-dependent cell-
mediated cytotoxicity (ADCC), a process that could be det-
rimental to the activation of T effector cells. After approval
of nivolumab for the treatment of non-small cell lung car-
cinoma (NSCLC) in 2015, the first immunotherapy com-
bination of ipilimumab plus nivolumab was granted
approval later in 2015, again in advanced melanoma [5].
More recently, the FDA approved three new ICIs, ate-
zolizumab, durvalumab and avelumab, all of which are
antibodies directed against the protein programmed
death-ligand 1 (PD-L1). Both atezolizumab and durvalu-
mab are engineered IgG1 mAbs that include Fc modifica-
tions that eliminate ADCC, while avelumab includes a
wildtype IgG1 framework with intact ADCC. Since May
2016, atezolizumab and durvalumab have both been ap-
proved for the treatment of NSCLC and urothelial carcin-
oma, and avelumab was approved for use in Merkel cell
carcinoma and urothelial carcinoma [79].
Immune-related adverse events (irAEs) are discrete
toxicities caused by non-specific activation of the im-
mune system, and can affect almost any organ system.
In some studies, the reported incidence is as high as 90%
for any-grade irAEs due to single-agent ICI therapy [10],
but meta-analysis indicates an overall incidence <75% with
anti-CTLA-4 monotherapy (ipilimumab) [11], and 30% in
phase 3 trials of anti-PD-1/PD-L1 agents [1214]. IrAEs
grade 3 severity occur in up to 43% of patients taking
ipilimumab [10] and 20% taking PD-1/PD-L1 agents
[12, 15]. The incidence of irAEs with ipilimumab and
pembrolizumab is dose-dependent, with greater toxicity at
higher dose levels; toxicity also varies between the adju-
vant and metastatic disease settings [10, 1619]. There is
significant variance in definitions of toxicity severity across
disciplines, as well as variation in how symptoms and
signs that may be attributable to the same underlying
pathophysiology are reported. This causes considerable
difficulty in obtaining accurate data on incidence and
prevalence based on clinical trials [12]. Nonetheless, the
incidence of most irAEs with ICI monotherapy appears to
be broadly similar across tumor types [12]. Some of the
mechanisms that underpin the development of inflamma-
tory toxicity in particular those driven by CD8 T cell
activity overlap with those responsible for the drugs
therapeutic effects. However, the exact pathogenesis of
immune toxicity is not clear, and many other inflamma-
tory cells, such as Th17 and other types of cells, are re-
ported to be involved. The mechanism of toxicity may
also vary by ICI, and may ultimately affect acuity, chron-
icity and management. In some cases, irAEs may occur in
patients with durable responses to treatment; this associ-
ation has not been fully ascertained [20, 21].
With increasing patient exposure to immunotherapy,
the nature and range of irAEs is becoming more clearly
defined, and several new but serious adverse events have
been reported [22]. Skin, gut, endocrine, lung and muscu-
loskeletal irAEs are relatively common, whereas, cardiovas-
cular, hematologic, renal, neurologic and ophthalmologic
irAEs are well-recognized but occur much less frequently
(Fig. 1). Although the majority of irAEs are mild to moder-
ate in severity, serious, occasionally life-threatening irAEs
(e.g., severe colitis, pneumonitis, encephalitis, toxic epider-
mal necrolysis, myocarditis, and autoimmune type I dia-
betes mellitus [T1DM] presenting as diabetic ketoacidosis),
are reported in the literature, and treatment-related deaths
have been reported in up to 2% of patients in clinical trials
[14, 23, 24]. As life-threatening irAEs are rare, and may
mimic other better-known conditions, there is growing
recognition of the need to educate both the oncology and
general medical communities in recognizing and institut-
ing urgent and appropriate treatment of these conditions.
Immune-related AEs resulting from immunotherapy can
have a delayed onset and prolonged duration compared to
adverse events resulting from chemotherapy (Fig. 2), in
part due to pharmacodynamic differences. Moreover, the
relationship between irAEs and dose/exposure remains to
be fully established [25]. As such, clinicians must remain
vigilant to the diverse clinical presentations of irAEs and
the possibility that patients maypresentwithirAEslatein
the course of treatment, and in some cases months or
even years after treatment discontinuation [26, 27].
Nonetheless, since diagnostic tests may be invasive and
potentially costly, investigations should be undertaken
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 2 of 28
judiciously and reserved for situations when the results
will guide patient management. Table 1 provides a list of
recommended tests to consider in all patients prior to ini-
tiating checkpoint inhibitor therapy.
Effective management of irAEs depends on early rec-
ognition and prompt intervention with immune suppres-
sion and/or immunomodulatory strategies appropriate
to the affected organ and the severity of toxicity. Special-
ist physicians, nurses and pharmacists familiar with
irAEs should be involved early, and hospitalization may
be necessary in serious (grade 4) or grade 3 irAEs that
do not respond to therapy, or to expedite work-up and
prevent complications from potentially life-threatening
irAEs [28]. Patient education on the potential for irAE
development is a key component of any pre-treatment
discussion with patients considered suitable candidates
for immunotherapy. It is also important to establish
physician networks to share outcomes of successful irAE
treatment strategies. Short-term adverse events due to
the use of moderate to high dose corticosteroids (e.g.,
opportunistic infections, sleep disturbance, gastritis, and
hypertension) should be anticipated. Patients receiving
long-term or high dose corticosteroids are at risk of de-
veloping diabetes mellitus and osteoporosis and should
receive vitamin D and calcium supplementation and, in
some cases, antibiotic prophylaxis [28]. However, con-
flicting reports on the associated between antibiotic use
and ICI efficacy pose as yet unanswered about whether
routine antimicrobial prophylaxis is appropriate in pa-
tients receiving ICIs [29, 30]. For steroid-refractory cases
and/or when steroid sparing is desirable, management
should be coordinated with disease specialists. Other im-
munomodulatory agents, such as infliximab, other
tumor necrosis factor inhibitors (TNFi), mycophenolate
mofetil, anti-thymocyte globulin (ATG), calcineurin in-
hibitors, methotrexate, or intravenous immunoglobulin
(IVIG) and plasmapharesis may be required. However,
besides TNFi for colitis, these immunosuppressive treat-
ments have not been evaluated in large numbers of pa-
tients. Some retrospective analyses suggest that use of
corticosteroids for the management of irAEs is not asso-
ciated with inferior results of therapy [31, 32] but, due
Fig. 1 Distribution of mild and severe immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy. [Adapted from [88]]
Fig. 2 Pharmacokinetic/pharmacodynamic differences between chemotherapy and immunotherapy. Reproduced with permission from [25].
Dotted blue line represents waning of the biological effects of immunotherapy over time, and solid blue line represents early or late toxic effects.
Horizontal dotted blue arrow therefore represents duration of immunotherapy treatment benefit
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 3 of 28
to confounding, the association of irAEs with immuno-
logic activity from immunosuppression, and with individ-
ual patient efficacy, is not clear. The effects of alternative
forms of immunosuppression on the efficacy of ICIs have
not yet been sufficiently studied.
As physicians, nurses and patients become aware of the
value of immune-based treatments, including the syner-
gies offered by combination immunotherapy strategies,
there is a pressing need for guidance on how to recognize,
report and manage irAEs that arise in the course of treat-
ment. The Common Terminology Criteria for Adverse
Events (CTCAE) [33], a descriptive lexicon of terms and
adverse event severity, was developed by the National
Cancer Institute (NCI) at the National Institutes of Health
(NIH), with the goal of standardizing AE reporting across
medical specialties. However, increasing use of immuno-
therapy has clarified limitations in how immune-related
toxicities are addressed and classified within the current
CTCAE, as well as in other databases such as the Medical
Dictionary for Regulatory Activities (MedDRA). Import-
antly, the need for formal pathways for reporting
suspected irAEs has also highlighted the tendency for
CTCAE grading to under- or over-estimate true irAE inci-
dence and/or severity [28]. In certain settings, such as with
rheumatologic irAEs, CTCAE criteria are difficult to apply
and do not allow accurate recording of the severity and
impact of irAEs, especially as conditions may become
chronic [34]. These shortcomings present an opportunity
to improve and streamline irAE reporting in the next
versions of CTCAE and MedDRA. Similarly, since drug
labels for FDA-approved checkpoint inhibitors are based
on clinical trial data for individual drugs and do not
always align across therapeutic class, clinicians need
multidisciplinary, broad perspective guidance on how to
manage organ-specific toxicities.
To this end, the Society for Immunotherapy of Cancer
(SITC) established a Toxicity Management Working Group
to develop consensus recommendations on management
of irAEs that develop following ICI therapy until evidence-
based data are available to inform clinical decision-making.
This report represents the outcome of a recent workshop
to standardize toxicity management. The results represent
consensus thinking by a multidisciplinary group of experts
in the field but should not replace sound clinical judgment
or personalized drug management, as immunotherapy pa-
tients often require highly individualized management.
Methods
Consensus group representation
In response to the need for a collaborative, multidisciplin-
ary approach to the management of ICI toxicities, the SITC
convened a one-day workshop on March 31st, 2017, in
Washington D.C. The meeting was a multi-stakeholder ef-
fort with participation from approximately 85 experts from
academia, government, industry, scientific organizations
and other related entities. Representation was sought from
medical oncologists, surgeons, disease subspecialists, basic
scientists, pharmacists, industry clinical, regulatory and
safety experts and nurses. In order to streamline recom-
mendations across the range of organizations active in
the area of cancer immunotherapy, SITC invited rep-
resentatives from the American Society of Clinical
Table 1 Pre-treatment evaluation and diagnostic tests to
consider in all patients prior to initiating checkpoint inhibitor
therapy
Routine pre-treatment screening
History
Detailed questioning for autoimmune, infectious disease, endocrine
and organ-specific disease history
History of base line bowel habit (frequency of bowel movements,
usual stool consistency)
Blood tests
CBC
CMP
TSH
HbA1c
Free T4
Total CK
Infectious disease screen: HBsAg, HBsAb, HBcAb, hCAb, CMV
antibody, T-spot test, HIV antibody, HIV antigen (p24)
a
Fasting lipid profile
Dermatologic examination
Full skin and mucosal exam, taking note of the extent and type of
lesions present
Pulmonary tests
Baseline oxygen saturation on room air and during ambulation
Cardiac tests
ECG
Troponin I or T: baseline and weekly for 6 weeks
b
Additional screening tests recommended in patients with pre-existing
organ disease/at risk of organ-specific toxicity
Endocrine tests
8 am cortisol
8 am ACTH
Cardiac tests
Brain natriuretic peptide (BNP) or N-terminal pro B-type natriuretic
peptide (NT pro-BNP)
Pulmonary tests
PFTs
c
6MWT
c
In certain settings, some of these tests may not be readily available. Until their use
is firmly supported by evidence, individual physician judgment is recommended
a
These tests become very relevant if patients develop irAEs and require
immunosuppressive treatment such as steroids and/or anti-TNFαtreatment
b
Given the rarity of cardiac toxicity, this may not be cost-effective as a routine
test. . Baseline troponin should be measured although the follow up interval
for re-testing is not determined. Any suspicious cardiopulmonary symptoms
warrant repeat troponin and natriuretic testing in this population
c
Given the rarity of pulmonary toxicity, pre-treatment PFTs and 6MWTs should
considered in patients with pre-existing lung disease (chronic obstructive
pulmonary disease, interstitial lung disease, sarcoidosis, pulmonary fibrosis
etc.) and may not be feasible in all patients
ACTH, Adrenocorticotropic hormone; CBC, Complete blood count; CMP,
Complete metabolic panel; CMV, Cytomegalovirus; CK, Creatine kinase; ECG,
Electrocardiogram; HbA1c, Glycosylated hemoglobin; HBsAg, Hepatitis B surface
antigen; HBsAb, Hepatitis B surface antibody; HBcAb, Hepatitis B core antibody;
HCAb, Hepatitis C antibody; HIV, Human Immunodeficiency Virus; PFTs,
Pulmonary function tests; TSH, Thyroid-stimulating hormone; T4, Thyroxine;
6MWT, 6 min walk test
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 4 of 28
Oncology (ASCO), National Comprehensive Cancer Net-
work (NCCN), Parker Institute for Cancer Immunother-
apy, Friends of Cancer Research, American Association
for Cancer Research (AACR), Association of Community
Cancer Centers (ACCC), NCI and the Oncology Nursing
Society (ONS) to participate in the workshop. To ensure
that commercial interests did not influence the outcomes
of the workshop, industry representatives participated in
group discussions but final approval of the workshop out-
put, and of this manuscript, was the responsibility of the
organizing committee, none of whom are employed by a
pharmaceutical or biotechnology company. Representa-
tives from the Office of Hematology and Oncology Prod-
ucts, Center for Drug Evaluation and Research (CDER),
were invited to review and provide feedback on the
final manuscript. Individuals selected as authors were
workshop organizers and lead discussants for individual
organ-specific toxicity breakout groups. All participants
were required to disclose any potential conflicts of interest
prior to participation.
Workshop objectives and procedures
The overarching goals of the workshop were twofold: 1)
to develop treatment algorithms for managing common
and rare immunotherapy-related toxicities and 2) to de-
velop standardized templates, including inclusion and
exclusion criteria, for irAE management in clinical trial
protocols (which will be reported separately). More
broadly, participants were charged with describing the
spectrum of immune-related toxicities and providing
recommendations on recognizing, monitoring and man-
aging these toxicities. To facilitate discussion among ex-
perts in different medical fields, attendees broke out into
11 subgroups (breakout groups) that focused on irAEs
identified by body system (dermatologic, gastrointestinal,
endocrine, pulmonary, rheumatologic, cardiovascular,
hematologic, renal, neurologic and ophthalmologic) as
well as infusion reactions. These breakout groups were
generally supplemented with disease subspecialty expert-
ise focused on the area of interest. Each breakout group
received instructions to guide their discussion, a list of
recognized toxicities by system, relevant drug package
inserts, several key supporting references, and a copy of
CTCAE version 4.0. A working draft of the Friends of
Cancer Research/Parker Institute for Cancer Immuno-
therapy guidelines on monitoring, management and
follow-up of irAEs from anti-PD-1/PD-L1 agents was
also distributed [35].
After separate breakout group discussions, one repre-
sentative from each group presented their recommenda-
tions to all participants, and responded to questions and
additional suggestions from the wider group. Following
the meeting, recommendations made on-site were recir-
culated by email to participants from each breakout
group to ensure all views and opinions were captured.
The final recommendations on management of irAEs
presented in this paper therefore represent the views of
each multidisciplinary expert group. These recommen-
dations are not intended to provide comprehensive med-
ical guidance on the management of disorders that may
arise from use of immunotherapy treatment; specialist
care should be sought as necessary, and as indicated in
treatment-specific guidelines.
Strengths and limitations of the consensus
recommendations
These consensus recommendations represent the views
of a broad range of experts from multiple fields of
expertise, and from large cancer organizations with differ-
ing areas of focus. In some cases they are driven by evi-
dence from the published literature; in others, particularly
where data are lacking, they are guided by accumulated
clinical experience and practice. The participation of
stakeholders from the pharmaceutical and biotechnology
industries is another strength, ensuring that those in-
volved in drug research and development are part of the
discussion and that there is access to large industry-
collected patient databases. However, it is important to ac-
knowledge that evidence gaps are considerable, consensus
was not reached on all issues, and many questions remain
unanswered. Furthermore, not all working groups had
representation from all specialist groups (oncologist, dis-
ease specialist, nurse, pharmacist). The recommendations
may not take into account reimbursement restrictions that
could limit access to recommended drugs for some pa-
tients. Lastly, but importantly, there was no patient repre-
sentation. Finally, the recommendations addressed in this
document reflect irAEs related to PD-1/PD-L1 and
CTLA-4 inhibitors, and do not address toxicity that may
ensue following administration of other classes of im-
munotherapy, including chimeric antigen receptor T cell
(CAR T) therapy. It is unclear to what extent the recom-
mendations can be generalized to immunotherapy agents
other than those addressed in this manuscript, including
agents in development.
Consensus recommendations
The recommendations for managing toxicities associated
with ICIs, below, represent the consensus views of par-
ticipants in the 11 body system groups. Overall, irAEs
are broken down into two major categories, based on
the opinions of the workshop organizers regarding the
frequency with which they are seen in clinical practice:
frequently reported (dermatologic, gastroenterological,
endocrine, respiratory, and rheumatologic/musculoskel-
etal) and uncommon (cardiovascular, hematologic, renal,
neurologic and ophthalmologic). Infusion reactions, which
are more common with mAbs based on a wildtype IgG1
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 5 of 28
backbone and less common with IgG4 antibodies, are also
addressed. Within each body system, information is di-
vided into three sections: clinical presentation and epi-
demiology, diagnostic evaluation, and guidance on when
to refer to a disease specialist.
Management of irAEs relies heavily on corticosteroids,
and other immunomodulatory agents, which should be
prescribed judiciously to reduce the potential for short
and long-term complications. It remains unclear whether
prophylactic antibiotics should routinely be prescribed to
reduce the potential for opportunistic infection in patients
receiving steroids. Broadly, corticosteroid management
can be approached as shown in Table 2, but treatment
should be individualized depending on each patientsmed-
ical history; co-morbidities; underlying disease status; type,
number and severity of adverse events; ICI administered;
and ability to tolerate corticosteroids.
Table 3 summarizes the recommended management of
recognized irAEs across body systems.
Frequently reported immune-related adverse events
Dermatologic adverse events
Clinical presentation and epidemiology Maculopapu-
lar rash and pruritus are common reactions to ICIs but
lichenoid, eczematous, and bullous dermatitis, and psoria-
sis have also been reported, albeit less frequently. Vitiligo
is frequently seen in the melanoma patient population.
Dermatologic toxicity (all grades) is reported in 3040%
of patients taking PD-1/PD-L1 inhibitors [13, 15], and
approximately 50% of patients treated with ipilimu-
mab [13]. A systematic review of the literature reported
that 1320% of patients taking pembrolizumab or nivolu-
mab developed rash or pruritus (all-grade) and approxi-
mately 8% (all with melanoma) developed vitiligo [36],
which is associated with tumor response [20]. More re-
cently, several cases of hair re-pigmentation have also been
described in patients treated with anti-PD1 or anti-PD-L1
therapy [37]. Onset of skin irAEs typically occurs within
days or weeks of treatment [38] although onset may be de-
layed, appearing after several months of treatment [39].
Most dermatologic irAEs are low-grade and manageable,
[13, 36] although rare, potentially life-threatening exfolia-
tive dermatological conditions such as Stevens-Johnson
Syndrome/toxic epidermal necrolysis (SJS/TEN), and drug
rash with eosinophilia and systemic symptoms (DRESS)
have been reported [28]. Severe irAEs tend to occur more
commonly with combination ICI therapy [40]. Any clinical
suspicion of such reactions should prompt immediate spe-
cialist referral. Permanent discontinuation of immunother-
apy is mandatory for grade 4 dermatologic irAEs, SJS/
TEN, or DRESS syndrome.
Diagnostic evaluation: Given the frequency and persist-
ence of skin toxicities with ICIs, dermatologic assess-
ments are warranted in patients with a known history of
immune-related skin disorders such as psoriasis, bullous
pemphigoid or lupus. Non-specific maculopapular erup-
tions are commonly reported, which may, in part, reflect
the limitations of CTCAE in the classification of specific
subsets of skin disorders. Whenever possible, the irAE
should be categorized since management algorithms re-
flect the approach to idiopathic skin disorders, beyond
systemic immune suppression with steroids. Patients
Table 2 General guidance for corticosteroid management of immune-related adverse events
Grade of immune-related AE
(CTCAE/equivalent)
Corticosteroid management Additional notes
1Corticosteroids not usually indicated Continue immunotherapy
2If indicated, start oral prednisone 0.5-1 mg/kg/day if patient
can take oral medication.
If IV required, start methylprednisolone 0.5-1 mg/kg/day IV
If no improvement in 23 days, increase corticosteroid dose to
2 mg/kg/day
Once improved to grade 1 AE, start 46 week steroid taper
Hold immunotherapy during corticosteroid use
Continue immunotherapy once resolved to grade
1 and off corticosteroids
Start proton pump inhibitor for GI prophylaxis
3Start prednisone 1-2 mg/kg/day (or equivalent dose of
methylprednisolone)
If no improvement in 23 days, add additional/alternative
immune suppressant
Once improved to grade 1, start 46-week steroid taper
Provide supportive treatment as needed
Hold immunotherapy; if symptoms do not improve
in 46 weeks, discontinue immunotherapy
Consider intravenous corticosteroids
Start proton pump inhibitor for GI prophylaxis
Add PCP prophylaxis if more than 3 weeks of
immunosuppression expected (>30 mg prednisone
or equivalent/day)
4Start prednisone 1-2 mg/kg/day (or equivalent dose of
methylprednisolone)
If no improvement in 23 days, add additional/alternative
immune suppressant, e.g., infliximab
Provide supportive care as needed
Discontinue immunotherapy
Continue intravenous corticosteroids
Start proton pump inhibitor for GI prophylaxis
Add PCP prophylaxis if more than 3 weeks of
immunosuppression expected (>30 mg prednisone
or equivalent/day)
Note: For steroid-refractory cases and/or when steroid sparing is desirable, management should be coordinated with disease specialists. AE, adverse event
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 6 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
DERMATOLOGIC Specialist referral?
Maculopapular rash/dermatitis
Grade Description Management
1 Macules/papules covering <10% BSA with
or without symptoms (e.g., pruritus, burning,
tightness)
Continue ICI
Oral antihistamines
Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
Topical corticosteroids
Class I topical corticosteroid (clobetasol propionate,
halobetasol propionate, betamethasone dipropionate cream
or ointment) for body; Class V/VI corticosteroid (aclometasone,
desonide, hydrocortisone 2.5% cream) for face
2 Macules/papules covering 1030% BSA with
or without symptoms (e.g., pruritus, burning,
tightness); limiting instrumental ADL
Continue ICI
Non-urgent dermatology referral
Oral antihistamines
Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
Topical corticosteroids (see grade 1)
As above
Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
3 Macules/papules covering >30% BSA with
or without associated symptoms; limiting
self-care ADL
Hold ICI
Same day dermatology consult
Rule out systemic hypersensitivity: CBC with differential, CMP
Oral antihistamines
Cetirizine/loratidine 10 mg daily (non-sedating);
hydroxyzine 10-25 mg QID, or at bedtime
Systemic corticosteroids
Prednisone 0.5 1 mg/kg/day (or equivalent dose of
methylprednisolone) until rash resolves to grade 1
Pruritus*
Grade Description Management
1 Mild or localized; topical intervention
indicated
Emollients with cream or ointment based, fragrance-free
products
Class I topical corticosteroid (clobetasol propionate,
halobetasol propionate, betamethasone dipropionate) for
body; Class V/VI corticosteroid (aclometasone, desonide,
hydrocortisone 2.5%) for face, AND oral antihistamines
(e.g., cetirizine/loratidine 10 mg daily, hydroxyzine 10-
25 mg QID, or at bedtime
2 Intense or widespread; intermittent; skin
changes from scratching (e.g., edema, papulation,
excoriation, lichenification, oozing/crusts); oral
intervention indicated; limiting instrumental ADL
Dermatology referral
Class I topical steroid (clobetasol propionate, halobetasol
propionate, betamethasone dipropionate) for body; class V/VI
steroid (aclometasone, desonide, hydrocortisone 2.5%) for face,
AND oral antihistamines (e.g., cetirizine/loratidine 10 mg daily,
hydroxyzine 10-25 mg QID, or at bedtime
Oral corticosteroids
Prednisone 0.5 1 mg/kg/day (or equivalent of
methylprednisolone) tapered over 2 weeks
3 Intense or widespread; constant; limiting
self-care ADL or sleep; oral corticosteroid
or immunosuppressive therapy indicated
Dermatology referral
GABA agonist (pregabalin, gabapentin 100-300 mg TID)
Oral corticosteroid
Prednisone 0.5 1 mg/kg/day (or equivalent of
methylprednisolone) tapered over 2 weeks
Notes:
1. Grade 4 maculopapular rash/dermatitis is not included in CTCAE
*Recommendations provided are based on case reports, series and expert consensus. Use of suggested therapies must be discussed with medical
oncology based on individual patient considerations. The impact of these therapies on the anti-tumor immune response and efficacy of cancer
treatment is unknown and requires further research.
GASTROENTEROLOGICAL Specialist referral?
Colitis
Grade CTCAE description Management
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 7 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
1 Asymptomatic; clinical or diagnostic
observations only; intervention not indicated
[Grade 1 diarrhea frequency 4/day]
Close follow up within 2448 h for changes or progression
Continue ICI
If symptoms persist, start routine stool and blood tests
Bland diet advisable during period of acute diarrhea
Anti-diarrheal medication is optional but not highly
recommended when infectious work-up is negative.
2 Abdominal pain; mucus or blood in stool
[Grade 2 diarrhea frequency 46/day]
Hold ICI
Outpatient stool and blood work; CRP, ESR, fecal calprotectin,
lactoferrin, imaging and endoscopy are optional
If diarrhea only, observe for 23 days. If no improvement start
prednisone 1 mg/kg/day (or equivalent dose of
methylprednisolone); anti-diarrheal medication is not
recommended
If diarrhea and colitis symptoms (abdominal pain +/blood in
BM), start prednisone 1 mg/kg/day (or equivalent dose of
methylprednisolone)immediately
If no improvement in 48 h, increase corticosteroid dose
to prednisone 2 mg/kg/day (or equivalent dose of
methylprednisolone)
If patient improves
Taper corticosteroid over 46 weeks may be needed
Resume ICI when corticosteroid is tapered to 10 mg/
day and patient remains symptom-free (grade 1)*
Continue anti-PD-1 or anti-PD-L1 monotherapy
If using combination anti-CTLA-4/anti-PD-1
immunotherapy, continue anti-PD-1 agent only
ICI dose reduction is not recommended
If colitis returns on resuming ICI:
Grade 2: temporarily hold ICI
Grade 3: permanently discontinue ICI
See note 5
3 and
4
Grade 3: Severe abdominal pain; change in
bowel habits; medical intervention indicated;
peritoneal signs
[Grade 3 diarrhea frequency 7×/day]
Grade 4: Life-threatening consequences;
urgent intervention indicated
Grade 3: withhold ICI; consider resuming ICI when
corticosteroid is tapered to 10 mg/day and patient remains
symptom-free (grade 1). Consider hospitalization
Grade 4: permanently discontinue ICI and hospitalize
Blood and stool infection work-up, inflammatory markers,
imaging, endoscopy and GI consult
Start intravenous prednisone 1-2 mg/kg/day (or equivalent
dose of methylprednisolone) immediately
If patient improves, follow instructions for If patient
improvesfor grade 2
If refractory or no improvement on IV corticosteroid, start
prednisone 2 mg/kg/day (or equivalent dose of
methylprednisolone) for 3 days
Consider other anti-inflammatory agents e.g. infliximab 5 mg/
kg, which can be given again after two weeks if a second dose
is needed. Vedolizumab may also be used (see Note 4 below).
Notes:
1. CBC with differential, CMP, ESR and CRP are recommended before starting immunotherapy, to provide baseline values for comparison over time.
Despite the association between elevated ESR and CRP and colitis, some insurance companies may not cover these tests.
2. There is no proven role for prophylactic corticosteroids (budesonide) to prevent GI irAEs [45,47].
3. Response to infliximab generally occurs within 13 days although some patients benefit from a second dose after 2 weeks. Prolonged oral
prednisone taper may be required after infliximab administration. Whether infliximab reduces the antitumor efficacy of ipilimumab remains
unknown [103].
4. Case reports of successful treatment of steroid-dependent immune-related colitis using vedolizumab indicate this may benefit certain patients.
5. A GI consult is warranted in any patient who meets criteria for grade 2 diarrhea/colitis with negative infectious stool work up.
Hepatitis
Grade CTCAE Description (Note 1) Management
1 AST, ALT > ULN -3xULN; total bilirubin >
ULN-1.5xULN
Continue ICI
CMP or hepatic function panel once weekly
If liver enzyme and function tests are stable, reduce frequency
of blood tests
2 AST, ALT >3- 5xULN; total bilirubin >
1.5 - 3xULN
Hold ICI
Rule out viral hepatitis, autoimmune disease, biliary obstruction,
new metastasis or thrombosis
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 8 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
Start prednisone 0.5-1 mg/kg/day (or equivalent dose of
methylprednisolone) with 4 week taper
Monitor CMP twice a week
Liver biopsy is optional
Resume ICI when corticosteroid taper to 10 mg/day (toxicity
grade 1)
3 and
4
AST, ALT >5xULN; total bilirubin >3xULN Permanently discontinue ICI
Monitor CMP every 12 days
Start prednisone 12 mg/kg/day
If refractory after 3 days, consider mycophenolate
If liver enzymes improve, taper corticosteroid over 4 weeks
Consider liver biopsy
Notes:
1. Liver enzyme levels stated here are not defined in CTCAE and are instead drawn from reference [104]
2. In patients with liver metastasis, ICI can be used at baseline liver profile equivalent to grade 2. If 50% elevation in AST/
ALT lasting for 1 week, permanently stop ICI.
ENDOCRINE Specialist referral?
Hypophysitis
Grade CTCAE Description* Management
1 Asymptomatic or mild symptoms; clinical
or diagnostic observations only; intervention
not indicated
Hold ICI if grade 2 irAE until work up is completed and
appropriate hormone replacement is started
If central adrenal insufficiency: start physiologic steroid replacement:
Hydrocortisone ~10 mg/m
2
(HC15mgam,5mgat3pm)
Periodic assessment (e.g., every 3 months in the first year,
every 6 months thereafter): clinical monitoring and
repeat hormone levels (am cortisol and ACTH and/or low
dose cosyntropin stimulation test) to assess recovery
If central hypothyroidism: start thyroid hormone (levothyroxine
1mcg/kg)
Repeat thyroid function testing 68 weeks after initiation
of thyroid hormone and then periodically (e.g., every
3 months in the first year and every 6 months thereafter)
to assess recovery
If central hypogonadism, repeat hormone levels in 23 months
and consider testosterone in men or HRT in women if
appropriate for cancer type
For severe/life-threatening symptoms such as adrenal crisis, severe
headache, visual field deficiency:
Hospitalize as appropriate.
High dose corticosteroid (prednisone 1 mg/kg/day) (or
equivalent dose of methylprednisolone) in the acute phase,
followed by taper over 1 month.
Adrenal crisis should be managed per standard guidelines.
If central hypothyroidism, replace thyroid hormone (see above)
after corticosteroids have been initiated
2 Moderate; minimal, local or noninvasive
intervention indicated; limiting age-
appropriate instrumental ADL
3 Severe or medically significant but not
immediately life-threatening; hospitalization
or prolongation of existing hospitalization
indicated; disabling; limiting self-care ADL
4 Life-threatening consequences; urgent
intervention indicated
Note: In the uncommon scenario of MRI findings without pituitary deficiency, consider high dose corticosteroids for prevention of hormonal
dysfunction.
* Hypophysitis is not defined in CTCAE Version 4.0. This classification is drawn from the CTCAE category Endocrine disorders Other.
Hypothyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only; intervention not indicated
Hold ICI for grade 3 irAEs
ICI can be continued after resolution of symptoms to grade 2
or better.
Start standard thyroid replacement therapy: initial dose can be
the full dose (1.6 mcg/kg) in young, healthy patients, but a
reduced dose of 25 -50mcg should be initiated in elderly
patients with known cardiovascular disease.
Repeat TSH and free T4 testing after 68 weeks and adjust
thyroid hormone dose accordingly. If TSH is above reference
range, increase thyroid hormone dose by 12.5 mcg to 25 mcg
After identification of the appropriate maintenance dose,
further evaluation is required every year, or sooner if patients
status changes
2 Symptomatic; thyroid replacement
indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL;
hospitalization indicated
4 Life-threatening consequences; urgent
intervention indicated
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 9 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
After identification of the appropriate maintenance dose,
further evaluation is required every year, or sooner if patients
status changes
Hyperthyroidism
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only; intervention not indicated
Hold ICI for grade 3 irAEs
Standard therapy for hyperthyroidism should be followed
Thyroiditis is self-limiting and has 2 phases:
In the hyperthyroid phase,patients may benefit from
beta blockers if symptomatic (e.g., atenolol 2550 mg
daily, titrate for HR < 90 if BP allows). Monitor closely with
regular symptom evaluation and free T4 testing every
2 weeks.
Introduce thyroid hormones (see hypothyroidism
management) if the patient becomes hypothyroid (low
free T4/T3, even if TSH is not elevated).
Gravesdisease should be treated per standard guidelines.
2 Symptomatic; thyroid suppression therapy
indicated; limiting instrumental ADL
3 Severe symptoms; limiting self-care ADL;
hospitalization indicated
4 Life-threatening consequences; urgent
intervention indicated
Note: High dose corticosteroids (1 mg/kg/day) are not routinely required.
Type 1 diabetes (CTCAE defines hyperglycemia not diabetes)
Grade CTCAE Description Management
1 Fasting glucose > ULN - 160 mg/dL
(>ULN - 8.9 mmol/L)
Type 1 DM with diabetic ketoacidosis: Hold ICI; hospitalize and
initiate treatment per standard guidelines.
Type 1 DM without diabetic ketoacidosis: Hold ICI for
hyperglycemia grade 3. Treat with insulin and continue ICI
when patient recovers to grade 1.
Treat with insulin per standard guidelines and restart ICI when
patient recovers to grade 1.
Provide patient education on diet and lifestyle modification,
and blood glucose testing
2 Fasting glucose >160250 mg/dL
(>8.913.9 mmol/L)
3 Fasting glucose >250500 mg/dL
(>13.927.8 mmol/L); hospitalization
indicated
4 Fasting glucose >500 mg/dL
(>27.8 mmol/L); life-threatening
consequences
PULMONARY Specialist referral?
Pneumonitis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only
Consider holding ICI
Consider pulmonary and infectious disease consultations
Reimage at least prior to every cycle of ICI treatment (at least
every 3 weeks)
If repeat imaging shows resolution of radiographic
findings, no further CT imaging is necessary; resume
therapy with close follow-up
If evidence of progression, treat at higher grade
If no change, consider continued therapy with close
follow-up for new symptoms
If symptoms develop, treat at higher grade
Self-monitor symptoms and oxygen saturation (using personal
pulse oximeter) every 23 days; weekly clinic visits
If chest imaging abnormalities resolve, consider resuming
treatment with close follow-up
2 Symptomatic; limiting instrumental ADL;
medical intervention indicated
Hold ICI
Consider hospitalization
Pulmonary consultation for bronchoscopy with
bronchoalveolar lavage. Consider biopsies for atypical lesions
Initiate methylprednisolone 1 mg/kg/day (IV or oral equivalent)
Day 23 of corticosteroids/supportive care: If symptoms
improve to grade 2, start slow steroid taper over >1 month.
If symptoms do not improve, or worsen, treat as grade 34
Consider drug re-challenge if symptoms and imaging
abnormalities resolve
(pulmonary and
infectious disease)
3 Severe symptoms; limiting self-care ADL;
oxygen indicated
Permanently discontinue ICI
Hospitalize; consider ICU care
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 10 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
Pulmonary consultation for bronchoscopy with
bronchoalveolar lavage. Consider biopsies for atypical lesions
Initiate methylprednisolone IV, 2 mg/kg/day
Day 23 of corticosteroids/supportive care:
If no clinical improvement, add infliximab or
cyclophosphamide, mycophenolate mofetil or IVIG
If clinical improvement: reduce corticosteroids to 1 mg/
kg/day and slowly taper over >2 months.
Drug re-challenge:
Grade 3: Consider drug re-challenge on a case-by-case
basis after discussions weighing risk/benefit with the
patient and only if symptoms and imaging abnormalities
resolve
Grade 4: Permanent y discontinue ICI
(pulmonary and
infectious disease)
4 Life-threatening respiratory compromise;
urgent intervention indicated (e.g., intubation)
Notes:
1. Consider prophylactic antibiotics for pneumocystis pneumonia (PCP) for patients receiving at least 20 mg methylprednisolone or equivalent for
4 weeks
2. Consider calcium and vitamin D supplementation with prolonged steroid use
3. All patients with grade 24 pneumonitis receiving steroids should also be on proton pump inhibitor therapy for GI prophylaxis
4. T-spot testing should be undertaken to exclude tuberculosis in any patient being considered for anti-TNF therapy, prior to starting anti-TNF
treatment.
Sarcoidosis
Grade CTCAE Description Management
1 Not defined in CTCAE Consider holding ICI
Close follow-up
Consider corticosteroids
Hold ICI
Consider corticosteroid therapy for patients with sarcoidosis
grade 2 or higher and any of the following:
progressive radiographic change
persistent and/or troublesome pulmonary symptoms
lung function deterioration: TLC decline of 10%, FVC
decline of 15%; DLCO decline of 20%
concomitant involvement of critical extrapulmonary
organ systems
sarcoid-related hypercalcemia
Corticosteroid dose: prednisone 1 mg/kg (or IV equivalent of
methylprednisolone) for grade 2 sarcoidosis or severe cases
requiring hospitalization. Taper steroids over 24 months,
depending on response
2
Notes: To date, there are no studies focusing on management of sarcoidosis as a side effect of checkpoint inhibitor therapy. Current
recommendations are based on clinical experience and case report publications.
RHEUMATOLOGIC/MUSCULOSKELETAL [78] Specialist referral?
Inflammatory arthritis
Grade CTCAE Description (Note 1) Management
1 Mild pain with inflammatory symptoms
(Note 2), erythema, or joint swelling (Note 3)
Continue ICI
Analgesics: NSAIDs: naproxen 500 mg BID or meloxicam 7.5
15 mg daily orally for 46 weeks
If NSAIDs ineffective, consider prednisone 1020 mg daily for
24 weeks
Consider intra-articular corticosteroid injection only if 2 joints
affected and low dose prednisone (10 mg/day) and NSAIDs
not effective
If no improvement in 24 weeks, escalate to grade 2
management
Conduct serial rheumatologic examinations (2 weeks, 4 weeks,
then 46 weekly) and functional assessment at follow-up
2 Moderate pain associated with signs
of inflammation, erythema, or joint
swelling; limiting instrumental ADL
Consider holding ICI
Rheumatology referral to confirm inflammatory arthritis, assess
need for intra-articular injection and examine for signs of early
bone damage
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 11 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
Prednisone 20 mg daily for 24 weeks, increase to 1 mg/kg/
day, or equivalent. If no response in 24 weeks. Escalate to
grade 3 management
If symptoms improve, taper corticosteroid over 48 weeks or
until grade 1
3 Severe pain associated with signs of
inflammation, erythema, or joint
swelling; irreversible joint damage (e.g.,
erosion); disabling; limiting self-care ADL
Hold ICI
Rheumatology referral
Prednisone 1 mg/kg/day or equivalent for 24 weeks, or until
symptoms improve to grade 1
Consider additional immunosuppression (Note 4) (e.g.
methotrexate [Note 5], sulfasalazine, leflunomide). Consider
anti-cytokine therapy (e.g. TNF-inhibition) [Note 6]
If symptoms improve, taper corticosteroid over 48 weeks/until
grade 1; if symptoms do not improve in 46 weeks:
permanently discontinue ICI
Notes:
1. CTCAE includes separate listings for arthritis, joint effusion and arthralgia although there is overlap in presenting symptoms such as pain and
effects on ADL
2. Joint stiffness after sleep or inactivity, improvement of symptoms with movement or heat.
3. Joint swelling refers to the clinical finding on examination, and may encompass soft tissue swelling, joint effusion or synovitis.
4. Before initiation of these drugs, screening for hepatitis B and C should be performed
5. Methotrexate should be administered at a starting dose of 15 mg weekly, with daily folic acid supplementation. Titrate up to a maximum of
25 mg weekly, or switch to injectable methotrexate if patient cannot tolerate orally
6. Before anti-cytokine therapy, evaluation for latent/active TB should be performed
INFUSION REACTIONS Specialist referral?
Grade CTCAE Description Management
1 Mild transient reaction; infusion interruption
not indicated; intervention not indicated
Drug infusion rate may be decreased, or infusion temporarily
interrupted, until resolution of the event
Consider reducing the rate of infusion upon re-initiation or
subsequent infusions
Non-steroidal anti-inflammatory drugs (NSAIDs, e.g. acetamino-
phen), antihistamines, opioids, and corticosteroids may be used
per investigator/ institutional guidelines
Consider premedication for subsequent infusions per
investigator/ institutional guidelines
2 Therapy or infusion interruption indicated
but responds promptly to symptomatic
treatment (e.g., antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic medications
indicated for 24 h.
3 Prolonged (e.g., not rapidly responsive to
symptomatic medication and/or brief
interruption of infusion); recurrence of
symptoms following initial improvement;
hospitalization indicated for clinical sequelae
Permanently discontinue ICI
For severe/life-threatening reactions, manage the patient as
clinically appropriate (e.g. antihistamines, oxygen, fluids,
opioids, corticosteroids, bronchodilators, etc.) per investigator/
institutional guidelines
Refer to allergist to
prevent potential future
reactions
4 Life-threatening consequences; urgent
intervention indicated
CARDIOVASCULAR Specialist referral?
Grade CTCAE Description Management
1 Abnormal cardiac biomarker testing,
including abnormal ECG
Recommend baseline ECG and cardiac biomarker assessment
(BNP, troponin) to establish if there is a notable change during
therapy
Mild abnormalities should be observed closely during therapy
if abnormal
2 Abnormal screening tests with mild
symptoms
Control cardiac diseases (e.g. heart failure, atrial fibrillation)
optimally
Control cardiac disease risk factors proactively (including
hypertension, hyperlipidemia, discontinue smoking, and
monitor diabetes)
3 Moderately abnormal testing or
symptoms with mild activity
BNP > 500 pg/ml, troponin >99% institutional normal, new ECG
findings (QTc prolongation, new conduction disease, or ST-T
wave changes)
Consider withholding ICI
If a period of stabilization is achieved and definite cardiac
toxicity was not identified, it may be reasonable to consider
re-challenging the patient with ICI, with heightened
monitoring.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 12 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
If confirmed cardiac injury or decompensation, hold ICI therapy
until stabilized.
Optimally treat identified cardiac conditions
Consider corticosteroids if myocarditis suspected (Note 2)
4 Moderate to severe decompensation,
intravenous medication or intervention
required, life threatening conditions
Permanently discontinue ICI
If myocarditis is identified, consider high-dose corticosteroids
(1 mg/kg methylprednisolone (IV) for at least several days) until
improved to grade 1, after that consider at least 45 weeks
of tapering doses (Note 2).
Add additional immunosuppressive agents in severe refractory
cases.
Give additional supportive treatments, including appropriate
treatment of heart failure. Additional treatment of detected
cardiac conditions should be provided.*
Notes:
1. Grades outlined here are not drawn from CTCAE.
2. Patients with confirmed myocarditis (or in cases of reasonable suspicion) should receive emergent high-dose corticosteroids. Until data are
available (e.g., cut-off levels of troponin) to determine when to start corticosteroids in patients with possible (as opposed to confirmed)
myocarditis, this decision should be made on a case by case basis. The importance of active, ongoing consultation with a cardiologist to discuss
the risk/benefit of continuing ICI therapy, starting corticosteroids, or instituting other cardiac treatments, cannot be overstated.
* Other therapies for management of myocarditis or pericarditis (viral based therapy, immunoglobulins, or plasmapheresis) are speculative at this
point in time.
HEMATOLOGIC Specialist referral?
Anemia
Grade CTCAE Description Management
1 Hgb < LLN - 10.0 g/dL; <LLN - 6.2 mmol/L;
<LLN - 100 g/L
Monitor closely while continuing ICI
2 Hgb <10.08.0 g/dL; <6.24.9 mmol/L;
<100 - 80 g/L
Monitor closely while continuing ICI
Evaluate for possible causes and refer to hematology if no
obvious cause if identified
if no cause identified
3 Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L;
transfusion indicated
Hold ICI
Consider Coombs testing and evaluation for hemolytic anemia
Consider re-treating with ICI if hemolytic anemia responds
promptly (within a few days) to corticosteroids
4 Life-threatening consequences; urgent
intervention indicated
Permanently discontinue ICI
Notes:
1. No firm recommendations for corticosteroid management are provided here as treatment should be individualized.
2. If unexplained anemia does not respond to steroids, consider bone marrow biopsy.
Thrombocytopenia (CTCAE defines decreased platelet count not thrombocytopenia)
Grade CTCAE Description Management
1 <LLN - 75,000/mm3; <LLN-75.0 x 10e9 /L Progressive or grade 3 unexplained thrombocytopenia: consider
work up for autoimmune disease and rule out DIC or other
cause of thrombocytopenia that may be related to underlying
disease
Precipitous development of thrombocytopenia: consider steroid
intervention pending clinical condition (brain metastases,
colitis, etc.) and evaluate for immune-mediated
thrombocytopenia
Permanently discontinue ICI for clinically significant, steroid-
refractory ICI-associated thrombocytopenia
2 <75,00050,000/mm3; <75.050.0 x 10e9 /L
if no cause identified
3 <50,00025,000/mm3; <50.025.0 x 10e9 /L
4 <25,000/mm3; <25.0 x 10e9 /L
Note: No firm recommendations for corticosteroid management are provided here as treatment should be individualized.
RENAL Specialist referral?
Nephritis
Grade CTCAE Description Management
1 Creatinine level increase of >0.3 mg/dL;
creatinine 1.52.0× above baseline
Continue ICI but initiate work-up to evaluate possible causes
and monitor closely
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 13 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
2 Creatinine 2 - 3× above baseline Hold ICI
Resume when creatinine decreased to grade 1 (Note 2)
Consider timing of event and response to treatment when
making a decision
Start corticosteroids (Note 3)
Discontinue ICI for persistent or recurrent elevation
3 Creatinine >3 x baseline or >4.0 mg/dL;
hospitalization indicated
Hold ICI
Consider resuming treatment if grade 3 resolves (Note 2) and
cause of event is confirmed. Timing of event and response to
treatment should be considered in making a decision
Start corticosteroids (Note 3)
Discontinue ICI for persistent or recurrent elevation
4 Life-threatening consequences; dialysis
indicated
Permanently discontinue ICI
Start corticosteroids (Note 3)
Notes:
1. Grades are those listed under acute kidney injuryin CTCAE [33].
2. Consider using increase from baseline rather than absolute value for creatinine monitoring, especially in patients with primary renal carcinoma or
other baseline renal conditions.
3. For persistent creatinine elevation grade 2 with no other identifiable cause, start corticosteroids. Dose and schedule should be individualized
and based on grade. Taper corticosteroids when creatinine improves to grade 1.
NEUROLOGIC Specialist referral?
Encephalopathy/Leukoencephalopathy/Reversible posterior leukoencephalopathy syndrome (PRES)
Grade CTCAE Description Management
1 Mild symptoms Hold ICI and initiate diagnostic work-up
Consider permanent discontinuation of ICI if AE worsens or
does not improve
2 Moderate symptoms; limiting instrumental ADL Hold ICI
Start 0.51.0 mg/kg/day methylprednisolone equivalents PO or
IV once infection has been excluded
Consider permanent discontinuation of ICI if AE worsens or
does not improve.
3 Severe symptoms; limiting self-care ADL Permanently discontinue ICI
Start 12 mg/kg/day methylprednisolone equivalents IV and
prophylactic antibiotics
Consider plasmapheresis if no improvement or symptoms
worsen after 3 days
4 Life-threatening consequences; urgent
intervention indicated
Permanently discontinue ICI
Start 12 mg/kg/day methylprednisolone equivalents IV and
prophylactic antibiotics
Consider plasmapheresis if no improvement or symptoms
worsen after 3 days
Contact intensive care unit
and contact intensive
care unit
Notes: CTCAE provides grading criteria for encephalopathy, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (PRES). For
all these irAEs, ICI therapy may be continued for grade 1 irAEs. However, grade 2 events require an ICI hold, and referral to neurology. For events
of grade 3 severity, ICI should be permanently discontinued, IV corticosteroids administered, and plasmapheresis considered if there is no
improvement, or symptoms worsen, after 3 days.
Peripheral motor and sensory neuropathy
Grade CTCAE Description Management
1 See CTCAE for grade definitions for
each disorder
Continue ICI
Consider permanent discontinuation of ICI if AE worsens or
does not improve
2Hold ICI
Refer to neurology
Consider permanent discontinuation of ICI if AE worsens or
does not improve
3Permanently discontinue ICI
Start 12 mg/kg/day methylprednisolone equivalents IV, and
prophylactic antibiotics
4
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 14 of 28
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
Notes: CTCAE provides grading criteria for peripheral motor neuropathy and sensory motor neuropathy. For all these irAEs, ICI therapy may be
continued for grade 1 irAEs. However, grade 2 events require an ICI hold and referral to neurology. For events of grade 3 severity, ICI therapy
should be permanently discontinued and IV corticosteroids administered.
OPHTHALMOLOGIC
Uveitis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only
Continue ICI
Ophthalmology referral within 1 week
Start lubrication drops (artificial tears)
2 Anterior uveitis; medical intervention
indicated
Hold ICI
Ophthalmology referral within 2 days, prior to initiating uveitis
treatment
Coordinate treatment with ophthalmologist (topical
corticosteroids, cycloplegic agents, systemic corticosteroids)
3 Posterior or pan-uveitis (Note 1) Permanently discontinue ICI
In carefully selected cases it may be appropriate to restart
treatment, cautiously, depending on severity, systemic
response to immunotherapy and ocular response to topical,
local or systemic prednisone (prescribed in coordination with
ophthalmologist)
URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating treatment. Co-ordinate treatment with
specialists
Consider systemic corticosteroids in addition to intravitreal/
periocular corticosteroids/topical corticosteroid treatment as
recommended by ophthalmologist
URGENT
4 Blindness (20/200 or worse) in the
affected eye
Permanently discontinue ICI
URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating any treatment. Co-ordinate treatment with
specialists
Consider systemic corticosteroids in addition to intravitreal
/periocular corticosteroids/topical corticosteroid treatment as
recommended by ophthalmologist
URGENT
Note: Unlike anterior uveitis, posterior uveitis can be asymptomatic but nonetheless proceed to visual loss.
Episcleritis
Grade CTCAE Description Management
1 Asymptomatic; clinical or diagnostic
observations only
Continue ICI
Ophthalmology referral within 1 week
Start lubrication drops (artificial tears)
2 Symptomatic, limiting instrumental ADL;
moderate decrease in visual acuity
(20/40 or better)
Hold ICI
Ophthalmology referral within 2 days, prior to initiating uveitis
treatment
Coordinate treatment with ophthalmologist (topical steroids,
cycloplegic agents, systemic steroids) (See Note)
3 Symptomatic, limiting self- care ADL;
marked decrease in visual acuity
(worse than 20/40)
Permanently discontinue ICI
In carefully selected cases it may be appropriate to restart
treatment, cautiously, depending on severity, systemic
response to immunotherapy and ocular response to topical,
local or systemic prednisone (prescribed in coordination with
ophthalmologist)
URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating treatment (See Note). Co-ordinate treatment
with specialists.
Consider systemic steroids in addition to intravitreal /periocular
steroids /topical steroid treatment as recommended by
ophthalmologist
URGENT
4 Blindness (20/200 or worse) in the
affected eye
Permanently discontinue ICI
URGENT ophthalmology referral (preferably uveitis specialist)
prior to initiating any treatment (See Note). Co-ordinate
treatment with specialists.
URGENT
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 15 of 28
should undergo full skin and mucosal exam, taking note
of the extent and type of lesions present.
When to refer In cases of non-urgent or emergent refer-
ral, photographic documentation is recommended when a
new dermatologic manifestation appears, prior to imple-
menting treatment. This facilitates later classification of the
AE when necessary. A same-day dermatology consult is
warranted in any patient with blisters covering 1% body
surface area (BSA), a rash with mucosal involvement, any
rash covering 30% BSA, and rash with skin pain with or
without blisters (excluding dermatomal varicella zoster).
For these latter cases, skin biopsy is recommended to help
classify the event. Non-acute dermatology referral is rec-
ommended for rashes where diagnosis is unclear, grade 2
rash that is worsening, erythema multiforme, blistering dis-
orders of any BSA or for a rash consistent with psoriasis or
lichenoid dermatitis that has not responded to topical
intervention. Any grade 3 dermatologic toxicity warrants a
same-day dermatology consult. Patients with suspected
SJS/TEN, severe mucocutaneous reactions characterized
by epidermal necrosis and detachment, should be hospital-
ized immediately and a dermatologist consulted for admin-
istration of systemic immunosuppression.
The recommended management of common dermato-
logic irAEs is presented in Table 3; recommendations for
managing uncommon dermatologic irAEs is presented
in Additional file 1:Table S1.
Gastrointestinal adverse events
Clinical presentation and epidemiology
Colitis
Diarrhea is one of the most frequently reported irAEs in
patients taking ICIs. Mild, transient, self-limited diarrhea
that occurs on initiation of an immune response should
be distinguished from other presentations. Onset occurs
after an average of three infusions [11], although it may
occcur as soon as following the first infusion. Incidence is
higher among patients taking combination anti-CTLA-4/
anti-PD-1 therapy (44%) than those receiving anti-CTLA-
4(2333%) or anti-PD-1 (19%) monotherapy. The com-
binatorial approach is also associated with increased risk
of grade 3/4 symptoms compared with monotherapy, and
the proportion of patients experiencing high-grade symp-
toms is greater with ipilimumab than anti-PD-1 or anti-
PD-L1 agents [15, 40, 41]. The presence of diarrhea in
conjunction with abdominal pain, rectal bleeding, mucus
in the stool, and fever should alert the clinician to the
possibility of colitis, a potentially serious or even life-
threatening gastrointestinal (GI) complication of ICI ther-
apy. Reports differ on the primary location of ICI colitis,
with some finding a uniform distribution [42], and others
observing that inflammation preferentially affects the
descending colon [43, 44], although this may be due to
less frequent examination of the proximal colon [44, 45].
Diarrhea and/or colitis may recur months after discon-
tinuation of immunotherapy and can mimic chronic in-
flammatory bowel disease (IBD) [42, 46].
Hepatitis
Less frequently observed, but nonetheless well-recognized
in patients treated with ICIs, is a typically asymptomatic
immune-related hepatitis characterized by elevated ala-
nine aminotransferase (ALT) or aspartate aminotransfer-
ase (AST), with or without raised bilirubin. Median onset
of transaminase elevation is approximately 614 weeks
after starting ICI treatment [28]. A minority of patients
present with fever. The incidence of any-grade hepatic en-
zyme disturbance with ipilimumab 3 mg/kg monotherapy
is <4% and up to 15% when dosed at 10 mg/kg [24, 47].
Incidence of hepatitis in patients treated with anti-PD-1
ICIs is approximately 5%, but this rises to 30% in
patients treated with combination ipilimumab and
nivolumab [13, 28].
Table 3 Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy
(Continued)
Consider systemic steroids in addition to intravitreal /periocular
steroids /topical steroid treatment as recommended by
ophthalmologist
Notes: IMPORTANT: Starting treatment with steroids prior to conducting an eye exam may worsen ocular conditions that are due to infection (e.g.,
herpetic keratitis/uveitis) or may mask accurate diagnosis and severity grading when the patient is examined by an ophthalmologist.
Blepharitis
Grade CTCAE Diagnosis Management
Not defined in CTCAE Puffy eyelids may indicate early preseptal cellulitis, which
requires systemic antibiotic treatment. Warning signs (eyelid
swelling with pain and erythema, proptosis, pain with eye
movements, movement restriction/diplopia, vision changes)
should prompt urgent ophthalmology referral
In the absence of warning signs, start warm compresses and
lubrication drops and refer to ophthalmology, especially if
symptoms do not improve
URGENT if warning
signs
[Note: Recommended management of uncommon dermatologic immune-related adverse events is presented in Additional file 1: Table S1]
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 16 of 28
Acute pancreatitis has been reported but is rare [42];
asymptomatic elevation of lipase and amylase are more
common. The role of the gut microbiome in determin-
ing treatment response and risk of toxicities, including
colitis, in patients treated with ICIs is an area of active
investigation.
Diagnostic evaluation
In the setting of acute diarrhea, initial evaluation should
exclude an infectious etiology (consider stool culture,
Clostridium difficile, cytomegalovirus (CMV) DNA poly-
merase chain reaction (PCR), stool ova and parasites).
Inflammatory markers (fecal leukocytes/lactoferrin, fecal
calprotectin) and fecal occult blood test (FOBT) may
help indicate whether there is an inflammatory process
underlying the diarrhea. Screening tests for tuberculosis,
human immunodeficiency virus (HIV) and hepatitis A
and B should be considered if there is potential for use
of systemic immunosuppression e.g. infliximab in the
near future. Based on the IBD literature, risk of hepatitis
C exacerbation is minimal; as a result, testing for hepa-
titis C is not recommended [48, 49].
Colitis
Radiologically, two distinct patterns of anti-CTLA-4-as-
sociated colitis have been observed on computed tomog-
raphy (CT) imaging: a more common diffuse colitis
characterized by mesenteric vessel engorgement, and a
segmental colitis with moderate wall thickening and
associated pericolonic fat stranding in a segment of pre-
existing diverticulosis [50]. A fluorodeoxyglucose positron
emission tomography (FDG-PET)/CT study can also dem-
onstrate new FDG-avid diffuse colonic wall thickening in
patients with immune-related colitis [50]. Colonoscopy is
the most accurate means of evaluating the extent and se-
verity of colitis and is recommended in appropriate cases
since recent data suggest that the presence of ulceration
on endoscopy predicts steroid-refractory disease [51]. For
grade 2 diarrhea, systemic immunosuppression should
be initiated promptly after ruling out infectious etiology.
Colonoscopy can be considered if deemed clinically neces-
sary, although it is worth noting that certain types of
colitis may have a normal endoscopic appearance,
with significant inflammatory features on histology.
Therefore, routine mucosal biopsies should be per-
formed for histological examination. In addition, path-
ology with immunohistochemical staining to rule out
CMV infection is critical.
Histologically, colitis that follows treatment with anti-
CTLA-4 antibodies is characterized by neutrophilic in-
flammation with increased intraepithelial lymphocytes,
crypt epithelial cell apoptosis and few or no features of
chronicity. Similarly, anti-PD-1-related colitis typically
follows one of two patterns: active colitis with apoptosis
(active inflammation, neutrophilic crypt micro-abscesses,
increased crypt epithelial cell apoptosis, and presence of
crypt atrophy/dropout) or lymphocytic colitis (increased
intraepithelial lymphocytes in surface epithelium, surface
epithelial injury, and expansion of the lamina propria).
Pathological changes may also be visible outside the colon
in the duodenum, stomach and/or small bowel [52].
Hepatitis
Liver function testing prior to initiation of ICIs, and
again before each cycle of treatment, can help determine
patterns of liver enzyme disturbance. Hepatitis following
ICI therapy is typically detected on routine serum liver
function tests. Other causes of liver damage such as viral
infection, alcohol, other medications or cancer progres-
sion should be excluded. Other thromboembolic and
outflow obstructive etiology should also be excluded
through imaging. On radiologic evaluation, ipilimumab-
associated hepatitis has been shown to present with
non-specific and variable findings according to clinical
severity [53]. Hepatomegaly, edema and enlarged lymph
nodes in the periportal region, and attenuated liver paren-
chyma may be evident on CT and MRI. Liver biopsy, only
necessary in complicated cases, may reveal predominantly
hepatocyte injury (acute hepatitis pattern) with sinusoidal
histiocytic infiltrates, central hepatic vein damage and
endothelial inflammation similar to autoimmune hepatitis,
or predominant bile duct injury (biliary pattern, with por-
tal inflammation) [53, 54]; rarely, fibrin ring granulomas
have also been reported [55].
When to refer
If infectious work-up is negative, diarrhea due to previous
immunotherapy exposure should be considered a possible
etiology since colitis can wax and wane after an initial epi-
sode. Endoscopy and histology may provide further clarifi-
cation, and the patient should be referred promptly to a
gastroenterologist who is experienced managing patients
with gastrointestinal adverse events after immunotherapy.
There are reports about progression of colitis to chronic
IBD long term [56] and such patients should be followed
by a gastroenterologist long term.
Endocrine adverse events
Clinical presentation and epidemiology
The two most common endocrine irAEs are acute hypophy-
sitis resulting in hypopituitarism (central hypothyroidism,
central adrenal insufficiency, hypogonadotropic hypogonad-
ism), and thyroid disease or abnormalities in thyroid func-
tion tests (primary hypothyroidism and thyroiditis). Other
endocrinopathies such as primary adrenal insufficiency,
T1DM, hypercalcemia, and hypoparathyroidism have
been reported but are rare. The prevalence of these disor-
ders varies greatly. This may be due to the non-specific
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 17 of 28
presenting signs and symptoms, such as, headache, fatigue,
anorexia and nausea, coupled with the fact that hormonal
abnormalities are not uncommon in patients with advanced
cancer. Diagnosis is also complicated by the fact that base-
line screening for endocrine abnormalities is not routinely
performed (other than thyroid function tests, in some
cases), and corticosteroids may be initiated empirically
for suspected irAEs, which interferes with subsequent
endocrine testing. A low threshold of clinical suspi-
cion is therefore warranted and, in the absence of al-
ternateetiologies,adiagnosticwork-upforendocrine
dysfunction should be initiated.
Diagnostic evaluation
Routine monitoring for clinical signs and symptoms of
endocrinopathies, and patient education, are recom-
mended. All patients should be tested before starting treat-
ment for thyroid (thyroid-stimulating hormone [TSH]
and free thyroxine [freeT4]), early morning adrenal
(adrenocorticotropic hormone [ACTH] and cortisol)
function, and glycemic control (glucose and glycated
hemoglobin [HbA1c]). In situations where new elevation
in glucose is noted, testing for blood or urinary ketones
should be considered. Before each cycle, thyroid testing
TSH and free T4) should be repeated, along with a base-
line metabolic panel to allow monitoring of glycemic
trends.. Routine monitoring with early morning ACTH
and cortisol levels should be considered (every month for
6 months, then every 3 months for 6 months then every
6 months for 1 year).
Hypophysitis
Hypophysitis is most commonly seen with anti CTLA-4
antibody monotherapy (ipilimumab, with an incidence
of 10% at a dose of 3 mg/kg and up to 17% at
10 mg/kg), and with combination ipilimumab/nivolumab
(incidence 13%) [10, 13, 16, 17, 57]. The median time
from starting ipilimumab to diagnosis of hypophysitis is
89 weeks, or after the third dose of ipilimumab [15, 58].
Symptoms commonly include headache (85%) and fatigue
(66%); visual changes are uncommon. Clinical suspicion of
hypophysitis is frequently raised when routine thyroid
function testing shows a low TSH with low free T4,
suggestive of a central etiology. Patients have various
degrees of anterior pituitary hormonal deficiency, with
central hypothyroidism being most commonly seen
(>90%), followed by central adrenal insufficiency, which is
also found in the majority of patients [5961]. Both
central hypothyroidism and adrenal insufficiency occur
in >75% of patients and approximately 50% of patients
present with panhypopituitarism (adrenal insufficiency
plus hypothyroidism plus hypogonadism) [6163]. On
magnetic resonance imaging (MRI) of the sella, pituitary
enlargement can precede the development of clinical and
biochemical evidence of disease. MRI abnormalities, such
as stalk thickening, suprasellar convexity, heterogeneous
enhancement, and increased height of the gland as com-
pared with baseline scans (when available) are present in
most patients at the time of diagnosis. Resolution of pitu-
itary enlargement is common, with all cases resolved on
follow up scans after two months [60, 64].
All patients with suspected hypophysitis based on clin-
ical findings (headache, fatigue) or biochemical evalu-
ation (routine thyroid function testing showing low free
T4 with low/normal TSH) should undergo further test-
ing for diagnostic confirmation. Recommended tests,
preferably conducted in the morning around 8 am, in-
clude thyroid function (TSH, free T4), adrenal function
(ACTH, cortisol or 1 mcg cosyntropin stimulation test),
gonadal hormones (testosterone in men, estradiol in
women), follicle-stimulating hormone [FSH], luteinizing
hormone [LH]) and MRI of the sella, with pituitary cuts.
This should be done prior to administration of steroids.
Strict criteria for diagnostic confirmation of hypophysitis
are not currently available. Proposed confirmation cri-
teria include 1 pituitary hormone deficiency (TSH or
ACTH deficiency required) combined with an MRI ab-
normality, or 2 pituitary hormone deficiencies (TSH or
ACTH deficiency required) in the presence of headache
and other symptoms.
Management of confirmed hypophysitis includes re-
placement of deficient hormones (physiologic doses of ste-
roids and thyroid hormone). In the presence of both
adrenal insufficiency and hypothyroidism, steroids should
always be started prior to thyroid hormone in order to
avoid an adrenal crisis. High doses of steroids are necessary
in the setting of severe headaches, vision changes or ad-
renal crisis. Both adrenal insufficiency and hypothyroidism
appear to represent long term sequelae of hypophysi-
tis and lifelong hormonal replacement is needed in
most cases [59, 6466]. All patients with adrenal in-
sufficiency should be instructed to obtain and carry a
medical alert bracelet.
Thyroid dysfunction
Thyroid dysfunction (hypothyroidism, hyperthyroidism,
and thyroiditis) was reported in 620% of patients in
large phase 3 clinical trials.
Hypothyroidism
Patients with unexplained fatigue, weight gain, hair loss,
cold intolerance, constipation, depression and other rec-
ognized symptoms should be suspected of having
hypothyroidism. Lab tests showing high TSH and low
free T4 are indicative of biochemical hypothyroidism
and, if present, additional testing for thyroid antibodies
such as thyroid peroxidase (TPO) antibody is warranted.
Patients with confirmed hypothyroidism should be started
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 18 of 28
on thyroid hormone, with repeat TSH and free T4 levels
evaluated 68 weeks later. Once a maintenance dose is
identified (TSH within normal range) clinical and biochem-
ical re-evaluation should be undertaken every 12 months.
Thyrotoxicosis
Thyrotoxicosis (high free T4 or total T3 with low or nor-
mal TSH) may occur secondary to thyroiditis or Graves
disease. Thyroiditis is the most frequent cause of thyrotoxi-
cosis and is seen more commonly with anti-PD1/PD-L1
drugs than with anti-CTLA-4 agents; Gravesdisease is
very rare and occurs more commonly with anti-CTLA-4
drugs. Thyrotoxicosis due to thyroiditis may present with
weight loss, palpitations, heat intolerance, tremors, anxiety,
diarrhea and other symptoms of hypermetabolic activity,
although these symptoms may be masked if the patient is
taking beta-blockers. Most commonly, patients are asymp-
tomatic (painless thyroiditis) and routine laboratory moni-
toring shows high free T4 or triiodothyronine (T3) levels,
with low/normal TSH. A thyrotoxic phase occurs an aver-
age of one month after starting the drug. Additional tests
can be undertaken when thyroiditis is suspected, primarily
to rule out other causes of thyrotoxicosis such as Graves
disease. These include thyroid stimulating hormone recep-
tor antibody [TRAb] or thyroid stimulating immunoglobu-
lin (TSI) and TPO as well as images when feasible:
radioactive iodine uptake scan (RAIUS) or Technetium
(Tc)-99 m [pertechnetate] thyroid scan if recent iodinated
contrast was used. Thyroiditis is a self-limiting process and
leads to permanent hypothyroidism after an average
of 1 month after the thyrotoxic phase and 2 months
from initiation of immunotherapy. Conservative manage-
ment during the thyrotoxic phase of thyroiditis is sufficient.
Non-selective beta blockers, preferably with alpha receptor-
blocking capacity, may be needed in symptomatic patients.
Repeat thyroid hormone levels should be performed every
23 weeks and thyroid hormone replacement initiated at
thetimeofhypothyroidism diagnosis [59, 64].
Type 1 diabetes mellitus
Development of polyuria, polydipsia, weight loss, nausea
and/or vomiting should prompt investigation for possible
development or worsening of T1DM. Diagnosis and
management of T1DM is based on recognized guidelines
[67]. Tests for antibodies (glutamic acid decarboxylase
[GAD65], anti-insulin, anti-islet cell A, zinc transporter 8
[Zn-T8]), C-peptide and insulin could distinguish between
type 1 and type 2 disease.
When to refer
An endocrinology consultation is recommended in all
cases of suspected or confirmed hypophysitis, primary
hypothyroidism, hyperthyroidism, thyroiditis, type 1 DM
and all rare endocrinopathies.
Pulmonary adverse events
Clinical presentation and epidemiology
Pneumonitis
The most common lung toxicity observed in patients re-
ceiving ICI treatment is pneumonitis. The overall inci-
dence of pneumonitis associated with PD-1/PDL-1 and
CTLA-4-targeted therapies is <5%, with high-grade
(grade 3) events occurring in 12% of patients. Higher
rates have been reported for combinations of PD-1 and
CTLA-4 inhibitors [68]. These numbers are not clinic-
ally trivial, as pneumonitis is one of the most common
causes of ICI-related death. Moreover, the incidence of
pneumonitis is increasing as therapeutic indications for
ICIs expand, and more complex regimens are developed.
Pneumonitis may present on imaging studies as crypto-
genic organizing pneumonia (COP), nonspecific interstitial
pneumonitis (NSIP), hypersensitivity pneumonitis (HP), or
usual interstitial pneumonitis (UIP)/pulmonary fibrosis
(PF). Clinical and radiographic findings of ICI-related pneu-
monitis may closely mimic pneumonia, lymphangitic
spread of disease, cancer progression, and diffuse alveolar
hemorrhage. The radiographic appearance of pneumonitis
may be clinically asymptomatic or, alternatively, associated
with new or worsening shortness of breath, cough, wheez-
ing, chest pain, reduced exercise tolerance, fatigue with ac-
tivities of daily living (ADL) and new or increasing
requirement for supplementary oxygen. Acuity of onset
and severity may also vary, suggesting the importance of
vigilance and rapid response in some cases. Studies have
suggested a higher incidence of any grade (3.6% vs. 1.3%)
and severe (1.1% vs. 0.4%) pneumonitis with PD-1 inhibi-
tors compared with PD-L1 inhibitors [69]. Combination
therapies with anti-CTLA-4/anti-PD-1/PD-L1 immuno-
therapy and with ICI/cytotoxic combinations also confer a
higher risk of pneumonitis versus ICI monotherapy
[68, 70]. Higher rates of pneumonitis have also been re-
ported among ICI-treated patients with non-small cell lung
cancer (NSCLC) compared to patients with melanoma
[71]. Pneumonitis onset appears earlier in cases of NSCLC
(median [range]: 2.1 [0.227.4] months) versus melanoma
(median [range]: 5.2 [0.218.1] months) [72]. IrAEs associ-
ated with other organ systems, including hepatitis, colitis,
duodenitis, esophagitis, thyroiditis, hypophysitis, arthritis,
myositis, vitiligo, nephritis, and anemia may occur in up to
50% of patients and confound therapy. These irAEs may
occur concomitantly, precede or follow the development of
pneumonitis. In patients with preexisting lung diseases,
such as chronic obstructive pulmonary disease (COPD) or
PF, the diagnosis of pneumonitis is particularly challenging
and failure to recognize and treat pneumonitis in a timely
manner could lead to poor clinical outcomes.
In addition to pneumonitis, ICI therapy has been associ-
ated with pleural effusions, pulmonary sarcoidosis and
sarcoid-like granulomatous reactions. Sarcoid-like reactions
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 19 of 28
have been reported following both CTLA-4 and PD-1/PD-
L1-targeted therapies. Increased numbers of T helper 17
(Th17.1) cells are seen in the bronchoalveolar lavage
(BAL) fluid of these patients, suggesting that TH17 cells
may play an important role in the pathogenesis of this dis-
ease [73]. Sarcoidosis may be asymptomatic or present
with cough, wheezing, fatigue and/or chest pain. Data in
this area are scant at present, although case reports sug-
gest that the development of sarcoidosis may be associated
with prolonged cancer response [74, 75].
Treatment strategies for ICI related pneumonitis, based
on pneumonitis grade, are detailed in Table 3. Patients with
grades 12pneumonitismaybemanaged as outpatients
while those with pneumonitis grade 3 or higher typically re-
quire hospitalization. Drug withdrawal is the mainstay of
treatment for pneumonitis of all grades. For patients with
grade 1 pneumonitis, re-challenge following resolution of
infiltrates and close follow-up is reasonable. In these pa-
tients, symptoms should be monitored every 23 days. A
repeat chest CT should be performed prior to the next
scheduled dose of ICI and if the infiltrates have resolved,
ICI therapy may be cautiously resumed with close follow-
up. Bronchoscopy should be considered for evidence of
new or persistent infiltrates. Patients with grade 2 or higher
pneumonitis may require oral/intravenous corticosteroids.
Recrudescence of pneumonitis signs and symptoms has
been reported following rapid steroid taper; a minimum
46 week taper is therefore recommended. Additional im-
munosuppression with infliximab and/or cyclophospha-
mide is warranted among patients with recalcitrant disease.
Sarcoidosis
Once a diagnosis of sarcoidosis is established, immuno-
therapy should be withheld, particularly in patients with
extensive disease (stage 2), extrapulmonary disease in-
volving critical organ systems (ocular, myocardial, neuro-
logic, renal), or sarcoid-related hypercalcemia. Treatment
for irAE-related sarcoidosis should be considered if there
is 1) progressive radiographic change; 2) persistent and/or
troublesome pulmonary symptoms; 3) lung function de-
terioration (total lung capacity (TLC) decline of 10%,
forced vital capacity (FVC) decline of 15%; diffusing cap-
acity of the lungs for carbon monoxide (DLCO) de-
cline of 20%); 4) concomitant involvement of critical
extrapulmonary organ systems; or 5) sarcoid-related hyper-
calcemia. These guidelines are extrapolated from standard
management guidelines for sarcoidosis in the general
population. Further investigations of sarcoidosis manage-
ment in the ICI setting are needed.
Diagnostic evaluation
Pneumonitis
The diagnosis of pneumonitis is suggested by the presence
of new or progressive pulmonary infiltrates and ground
glass changes on lung imaging studies. The infiltrates are
typically bilateral, but may be asymmetric. CT imaging is
more reliable than chest radiographs in identifying these
changes, and is the imaging modality of choice. Baseline
and ongoing oxygen saturation (at rest and on ambula-
tion) should be monitored in all patients, as well as chest
CT, pulmonary function tests (PFTs), and a 6-min walk
test (6MWT). A pulmonology consult is warranted in any
patient with suspected pneumonitis. Atypical symptoms
such as fever and productive cough should also trigger an
infectious disease consultation. Fiberoptic bronchoscopy
with BAL may be helpful in excluding competing diagno-
ses. Lung biopsies are typically not warranted, but may be
useful in the setting of suspicious lesions and unexplained
lymphadenopathy.
Sarcoidosis
The diagnosis of pulmonary sarcoidosis is suggested by
radiographic evidence of intrathoracic lymphadenopathy
and irregular densities, coupled with histologic evidence
of epithelioid non-caseating granulomas obtained from
endobronchial ultrasound (EBUS), fine needle aspiration
(FNA) or transbronchial lung biopsy (TBBx). Since sar-
coidosis can mimic malignant disease progression, both
clinicians and radiologists should be aware of this possibil-
ity. Confirmation requires exclusion of infections and
other competing diagnoses. Patients may also present with
extrapulmonary manifestations of sarcoidosis. Therefore,
once the diagnosis is established an eye examination and
baseline electrocardiogram should be considered to inves-
tigate involvement of other organ systems. The natural
history of irAE-related sarcoidosis is not known and treat-
ment strategies for sarcoid in this setting have not been
established.
When to refer
Referral to a pulmonary specialist for bronchoscopy should
be pursued in all patients with radiographic and/or clinical
evidence of pneumonitis. Such evidence includes new pul-
monary infiltrates on lung imaging, or new or worsened
hypoxemia, dyspnea or cough. Unexplained lymphadenop-
athy or atypical pulmonary nodules and densities should
also prompt a pulmonary referral. Infectious disease
consultation should be considered for patients with
grade 2 pneumonitis. Long-term specialist follow-up is
also advisable in any patient with confirmed immune-
related lung disease.
Rheumatologic/musculoskeletal adverse events
Clinical presentation and epidemiology
Recognizing rheumatologic and musculoskeletal irAEs in
the oncology setting is challenging due to the broad range
of potential presenting symptoms and the prevalence of
musculoskeletal complaints in the general population.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 20 of 28
Although a paucity of epidemiological data limits our un-
derstanding of the true incidence of these irAEs, they are
increasingly reported across care settings. Since delayed
diagnosis and treatment can lead to long-term disability,
and disorders may become chronic and require ongoing
immunosuppressive/immunomodulatory therapy, it is im-
portant to understand typical symptom presentation and
recommended management. Preserving quality of life and
ability to perform ADL is a priority.
One of the most commonly reported rheumatologic
irAEs is an inflammatory oligo or polyarthritis that can
lead to rapid joint damage and may persist after discon-
tinuation of immunotherapy. Arthralgia has been re-
ported in approximately 15% of patients receiving ICIs,
but the incidence of inflammatory arthritis, which is
typically grade 2 or less, has not yet been systematically
reported [76]. Arthritis is rarely the sole irAE, with most
patients having other organ systems involvement. In a
small series, the median time to onset was five months
after starting ICI therapy. Clinically, three phenotypes
have been described: 1) predominantly large joint react-
ive arthritis that, on occasion, develops in association
with conjunctivitis and uveitis; 2) polyarthritis resem-
bling rheumatoid-like arthritis, affecting the small joints
of the hand (metacarpophalangeal [MCP], proximal in-
terphalangeal [PIP] joints or wrist), rarely associated
with typical rheumatoid factor (RF) or anti-citrullinated
protein antibodies (ACPA), but potentially erosive; and
3) seronegative, oligo and polyarthritis, typically starting
in the medium/large joints, characterized by synovitis
and involvement of tendons and entheses, with or without
joint erosions. Combination anti-CTLA-4/anti-PD-1 ther-
apy is associated with a greater risk of arthritis than mono-
therapy, although incidence is unaffected by drug or type
of malignancy. Management often requires moderate-dose
corticosteroids, sometimes in conjunction with steroid-
sparing immunomodulators and disease-modifying anti-
rheumatic drugs (DMARDs) including tumor necrosis
factor inhibitors (TNFi), methotrexate, leflunomide, sulfa-
salazine, and hydroxychloroquine. Persistence of inflamma-
tory arthritis up to two years after discontinuation of ICIs
has been seen, with ongoing requirement for immunomod-
ulatory therapy. Beyond arthritis, less commonly reported
rheumatologic irAEs recognized in the context of ICI ther-
apy include sicca, with severe eye and mouth dryness, and
parotitis; inflammatory myositis, most commonly resem-
bling polymyositis, occasionally resulting in rhabdomyoly-
sis; vasculitides including giant cell arteritis (GCA) and
polymyalgia rheumatica (PMR); systemic lupus erythema-
tosus (SLE) and sarcoidosis [76, 77].
One of the primary difficulties in ensuring accurate
reporting of rheumatologic irAEs is the nature of severity
grading in the current CTCAE. The current version (ver-
sion 4) classifies many clinically significant rheumatologic
events that require corticosteroids or immunomodulatory
treatment as grade 1/2, whereas the rheumatology
CTCAE (rCTCAE) compiled by the Outcome Measures
in Rheumatology network (formerly Outcome Measures
in Rheumatoid Arthritis Clinical Trials; OMERACT)
(RCTCAE version 2.0) [34] classifies similar symptoms
one or two severity grades higher. Of particular import-
ance, the current CTCAE classifies impairment in instru-
mental ADLs (taking medications, preparing meals,
housework, using transportation) as grade 2, despite the
fact that this represents a considerable degree of func-
tional disability and loss of independence. This also has
implications for the detection of clinically significant
musculoskeletal irAEs in clinical trial databases.
Current CTCAE terms for musculoskeletal symptoms
(e.g. arthritis and myositis) are not easily converted to
clinically relevant descriptors. Lack of precision may result
in diffusion of an irAE signal, distorting the epidemio-
logical landscape. For example, oncologists must choose
between several different codes to document a swollen
joint (joint effusion, joint pain, joint function, arthritis) or
muscle weakness (myalgia, muscle weakness, change in
lower extremity function). As such, it may be more appro-
priate to aggregate similar coding subtypes to better re-
flect the true incidence of musculoskeletal irAEs.
Diagnostic evaluation
A diagnostic algorithm for inflammatory arthritis has re-
cently been reported [78]. The SITC Toxicity Management
Working Group evaluated and discussed this algorithm and
made suggestions for its modification. The revisions are
noted below.
Grade 1: Joint examination (swelling/tenderness), func-
tional assessment, consider rheumatology referral, espe-
cially if symptoms persist.
Grade 2/3: Joint examination, functional assessment,
consider laboratory testing (antinuclear antibody [ANA]
rheumatoid factor [RF], cyclic citrullinated peptide anti-
body [anti-CCP], erythrocyte sedimentation rate [ESR]/
C-reactive protein [CRP]). Consider imaging (plain X-
ray of affected joints, joint MRI and/or musculoskeletal
ultrasound).
When to refer
All patients with CTCAE grade 2 inflammatory arthritis
should be referred to rheumatology. Also consider refer-
ring any patient whose symptoms persist for >6 weeks or
who requires >20 mg prednisone (or equivalent) daily that
cannot be tapered to <10 mg/day within 4 weeks [78]. All
patients with suspected myositis, presenting with muscle
weakness and elevated creatine kinase (CK), should be
referred to rheumatology or neurology, as this can be a
life-threatening adverse event.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 21 of 28
Because erosive, irreversible joint damage has been seen
within weeks of symptom onset, early involvement of rheu-
matologists is recommended to determine if additional
disease-modifying therapy beyond steroids is required.
For other suspected rheumatologic manifestations (e.g.
vasculitis, myositis, scleroderma, etc.), rheumatology re-
ferral is advisable even if the symptoms are mild, to en-
sure that appropriate diagnostic testing and optimal
management can be coordinated to prevent permanent
organ damage.
Infusion reactions
Clinical presentation and epidemiology
Infusion reactions may present with constitutional symp-
toms such as fever, rigor, pruritus, hypotension, dyspnea,
chest discomfort, rash, urticaria, angioedema, wheezing or
tachycardia, as well as the possibility of anaphylaxis re-
quiring urgent intervention. Infusion reactions (all grades)
are reported in 25% of patients receiving avelumab (pre-
medication with acetaminophen and an antihistamine is
recommended) [7] and in less than 10% of patients receiv-
ing other approved immune checkpoints inhibitors [59,
7981]. Infusions of ipilimumab appear to be well-
tolerated, with a low incidence (<6%) of infusion reactions
even when the infusion is delivered over 30 min (as op-
posed to the standard 90 min timeframe) when patients
are pre-medicated with diphenhydramine and/or cortico-
steroids [82]. Severe/life-threatening infusion reactions oc-
curred in less than 2% of the patients. Mild to moderate
reactions are managed with symptomatic treatment
and by reducing the rate or temporarily interrupting
the infusion [49]. Severe/life-threatening reactions
should be managed promptly and in accordance with
the institutional guideline for infusion reactions; perman-
ent discontinuation is recommended for such cases
(grades 3 or 4) [80].
Diagnostic evaluation
Infusion reactions are common to many cancer treat-
ments and appropriate training and procedures should
be in place while patients are receiving an immunother-
apy infusion. The severity of an infusion reaction should
be rapidly assessed and appropriate treatment imple-
mented in accordance with the institutional guideline.
Life-threatening reactions with hypoxia and/or shock
should be aggressively managed [80].
When to refer
Cancer patients often receive more than one drug during
infusion; patients with severe or life-threatening reac-
tions (CTCAE grade 3 or 4) should therefore be referred
to an allergist. Appropriate assessment and counseling
could prevent future re-exposure to drugs that have pre-
viously caused severe reactions.
Uncommon immune-related adverse events
Cardiovascular adverse events
Clinical presentation and epidemiology
Cardiac irAEs due to ICIs may present with non-specific
symptoms such as fatigue and weakness. However, more
typical cardiac symptoms of chest pain, shortness of
breath, pulmonary or lower extremity edema, palpita-
tions, irregular heartbeat, rapid onset of heart failure
symptoms or new heart block on electrocardiogram
(ECG) can occur at any time, more frequently within the
first few months of treatment. Other signs and symp-
toms may include muscle pain or syncope. Patients who
develop immune toxicities of other organ systems may
also develop cardiovascular toxicities, potentially with
symptoms that overlap with myositis (myalgias, rhabdo-
myolysis) or myocarditis or pericarditis (fever, chest pain
with inspiration, diffuse ST elevation on ECG), making
accurate diagnosis a considerable challenge. It is sug-
gested that there may be a link between rhabdomyolysis/
myositis, vasculitis and cardiac toxicity. However, myo-
carditis, pericarditis and cardiac dysfunction due to ICIs
are rare and the true incidence is unknown; current esti-
mates suggest less than 1% of patients [22]. Moreover, due
to varying definitions of cardiotoxicity [83], the obscurity
of CTCAE entries for some cardiac irAEs, especially myo-
carditis, and the absence of systematic monitoring or cod-
ing mechanism for cardiac events in immunotherapy
trials, cardiac irAEs are likely under-reported. In particu-
lar, myocarditis is a difficult diagnosis to make in any clin-
ical situation, but especially in a patient being actively
treated for cancer [84]. The expert consensus is to have
high vigilance for development of cardiac symptoms in all
patients, but especially in those with evidence of myocar-
ditis, vasculitis or myositis.
Cardiac irAEs are seen across the ICI drug class, with
higher incidence in patients taking combination anti-
CTLA-4/anti-PD-1 treatment compared to monotherapy.
Patients, including those with known cardiac comorbidi-
ties, should not be denied therapy with ICIs solely on the
basis of the potential for cardiotoxicity, but the level of
vigilance has to be raised. The non-specific presentation of
cardiac irAEs and potential to cause rapid clinical deterior-
ation with a higher than acceptable rate of mortality with
cardiac toxicity, make it imperative to maintain a low
threshold for clinical suspicion and early specialist referral.
Diagnostic evaluation
At baseline, prior to initiating ICI therapy, it is suggested
that a judicious combination of biomarkers (e.g., tropo-
nin I or T, brain natriuretic peptide [BNP] or N-terminal
pro B-type natriuretic peptide [NT pro-BNP], total CK,
fasting lipid profile, total CK and an electrocardiogram
[ECG] be evaluated in all patients). Myocarditis is very
rare but other potentially serious cardiac manifestations
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 22 of 28
(life-threatening rhythm disturbances and acute coron-
ary syndromes) are reported more commonly [85]. Since
the major indicator of suspicion for both myocarditis
and acute coronary syndrome is elevated troponin, a
fasting lipid profile serves as an important screening tool
to distinguish between atherosclerosis-related troponin
elevation and potential myocarditis. Two-dimensional
echocardiography (2-D Echo) may also be warranted in
high-risk patients with cardiac history, symptoms of
dyspnea, or if initial tests are abnormal. Serial ECGs
and cardiac biomarker testing should be considered,
particularly in patients with abnormal baseline investi-
gations or suspicious symptoms. There are no current
recommendations for the appropriate time interval
between tests. Patients who develop concerning symp-
toms while undergoing ICI therapy should have chest
imaging to exclude pulmonary embolism, pneumon-
itis, or pulmonary edema, as well as an ECG; cardiac
biomarkers done at baseline evaluation should be
retested. A repeat 2D Echo should be considered in
any patient who has significant dyspnea or abnormal
cardiac safety screening tests.
When to refer
An accurate baseline CV risk assessment should be
undertaken, including consultation with a cardiologist if
appropriate, in any patient who has multiple CV risk
factors or established CV disease at the onset of immune
therapy. Immediate referral is warranted for any patient
who develops abnormal cardiac test results during the
course of ICI therapy. Since myocarditis can rapidly lead
to death, patients with suspected or documented myo-
carditis should be admitted to the hospital for cardiac
monitoring. Patients with confirmed myocarditis should
receive emergent intervention with high dose corticoste-
roids, and immediate discontinuation of immunotherapy.
Until data are available (e.g., cut-off levels of troponin) to
determine when to start corticosteroids in patients with
possible (as opposed to confirmed) myocarditis, this deci-
sion should be made on a case by case basis. The import-
ance of active, ongoing consultation with a cardiologist to
discuss the risk/benefit of continuing ICI therapy, starting
steroids, or instituting other cardiac treatments, cannot be
overstated.
Hematologic adverse events
Clinical presentation and epidemiology
Although rare, hematologic irAEs have been described fol-
lowing ICI treatment and the literature includes case re-
ports of hemolytic anemia, red cell aplasia, neutropenia,
thrombocytopenia, myelodysplasia and hemophilia A
[15, 28, 86]. An active hematologic irAE also needs to
be distinguished from transient changes in laboratory
values that can occur during initiation of an immune
response. Post treatment lymphcytosis, eosinophilia, neu-
trophilia and monocytosis can be observed and are not typ-
ically clinically significant though some reports suggest they
maybeprognostic[87].Persistentposttreatmentcytope-
nias or progressive cytopenias should be evaluated for
autoimmune causes as well as with a peripheral smear, re-
ticulocyte count and assessment for hemolysis [88]. Causal
attribution is complicated by the fact that malignant disease
and its complications can also lead to cytopenias. Since the
CTCAE definition of thrombocytopenia describes absolute
platelet levels rather than an indication of changes in cell
number, it is not a reliable tool for evaluating potentially
life-threatening ICI-induced thrombocytopenia.
Diagnostic evaluation
Complete blood count (CBC) should be monitored at the
start of immune therapy, at intervals during treatment, and
periodically in long-term survivors who are no longer re-
ceiving treatment. Development of anemia should prompt
evaluation for common causes such as GI bleeding,
cancer-related anemia or cancer progression, or causative
drugs, including a work up for hemolysis. If the source of
anemia cannot be identified, bone marrow biopsy may be
indicated to rule out red cell aplasia. Similarly, any patient
who develops thrombocytopenia or neutropenia should be
evaluated for potential causes including medication-related
cell destruction or disease progression; in cases where an
obvious cause cannot be identified, an autoimmune cause
should be considered and investigated accordingly.
When to refer
In general, patients with unexplained cytopenias should
be referred to hematology for evaluation.
Renal adverse events
Clinical presentation and epidemiology
Overall, renal irAEs are considered rare, occurring in 2%
(ICI monotherapy) to 5% (combination ipilimumab/nivolu-
mab) of patients taking ICIs, with underlying pathology
only beginning to be characterized and reported [89, 90].
Most reports document isolated cases of interstitial neph-
ritis with specific agents and regimens, such as anti-PD-1
monotherapy, and combination anti-CTLA-4/PD-1 treat-
ment, in melanoma [91, 92]. Nephritis has not been associ-
ated with anti-PD-L1 monotherapy to date. Three cases of
acute renal failure were also reported during a study of
nivolumab and doublet platinum chemotherapy in NSCLC
[93]. There are also case reports of lupus nephritis [94] and
granulomatous nephritis [95, 96] following ipilimumab
treatment, and a single case of nephritis described after
treatment with avelumab [97]. However, recent data suggest
theincidenceofrenalirAEsmaybeunder-reportedwith
low-grade kidney injury affecting 2529% of patients taking
certain ICIs [90]. The onset of renal injury seen with PD-1
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 23 of 28
inhibitors usually occurs 310 months after initiation of
treatment, whereas irAEs secondary to anti-CTLA-4 agents
tend to have an earlier onset, after 23 months [90].
Renal toxicity from ICIs is usually asymptomatic, although
oliguria, hematuria, peripheral edema and anorexia are oc-
casionally reported. Management requires considerable
clinical judgment.
Diagnostic evaluation
Diagnosis of renal impairment may be complicated by
concomitant medications that precede, or are prescribed
during the course of, immunotherapy treatment. None-
theless, evidence of gradually rising serum creatinine
should prompt clinical suspicion. As such, serum cre-
atinine should be monitored on starting immunotherapy
treatment, and at intervals throughout the treatment
course. If creatinine remains elevated for >23 days,
monitor weekly (grade 1) or every 23 days (grade 2). It
is important to exclude other causes of renal dysfunction
through active inquiry about new medications, correc-
tion of dehydration and, possibly, additional investiga-
tions such as bladder and/or renal ultrasound, urinalysis,
assessment of serum electrolytes, or other studies based
on history. In suspected cases of immune-related renal
disease, renal biopsy should be considered to confirm
etiology and guide management. Because renal toxicity
typically resolves, treatment can resume if grade 23
adverse events resolve promptly, but therapy should be
discontinued in the face of persistent or recurrent grade
23 adverse events, or emergence of grade 4 toxicity. A
nephrology consult should be considered for any persist-
ent grade 3 renal impairment, or for recurrent renal
toxicity following a corticosteroid trial.
When to refer
A nephrology consult should be considered in patients
with persistent grade 23 elevation in creatinine, 3-fold
increase in creatinine over baseline, or whenever there is
evidence of metabolic change consistent with renal failure.
Neurologic adverse events
Clinical presentation and epidemiology
Neurologic irAEs are uncommon, with an overall inci-
dence of <4% following treatment with anti-CTLA-4
antibodies, 6% with anti-PD-1 antibodies, and 12% with
combination therapy involving both [98]. Most events
are mild and present with non-specific symptoms such
as headache; irAEs grade 3 or higher occur in <1% of
patients [98]. Examples of neurologic irAEs include auto-
immune encephalitis, myasthenic syndrome/myasthenia
gravis, Guillain-Barré syndrome, peripheral sensorimotor
neuropathies, Posterior Reversible Encephalopathy Syn-
drome (PRES), aseptic meningitis and transverse myelitis
[99]. Relevant CTCAE terms include encephalopathy,
leukoencephalopathy, peripheral motor neuropathy, per-
ipheral sensory neuropathy reversible posterior leukoence-
phalopathy syndrome, and nervous system not otherwise
specified. Common presenting features of autoimmune
encephalitis, meningitis and encephalopathy include al-
tered mental status, headache, seizures, focal neurologic
abnormalities and PRES.
Diagnostic evaluation
Diagnostic work-up should include history and physical
examination with full neurologic exam in all patients.
Evaluation of possible autoimmune encephalitis, menin-
gitis and encephalopathy should include lumbar punc-
ture and brain MRI, with and without contrast; it is
important to rule out infection, screen for unsuspected
central nervous system (CNS) metastasis and/or lepto-
meningeal spread. Paraneoplastic syndromes should also
be considered. Diagnostic evaluation of suspected per-
ipheral sensorimotor neuropathies should include differ-
ential diagnosis of disorders including, but not limited
to, diabetic neuropathy and vitamin B12 deficiency. Con-
sider imaging as appropriate, as well as nerve biopsy;
this is a diagnosis of exclusion, but in most cases it is a
clinical diagnosis.
When to refer
Neurology consultation is recommended for all neuro-
logic irAEs grade 2 and higher.
Ophthalmologic adverse events
Clinical presentation and epidemiology
Ocular irAEs, predominantly uveitis (anterior more com-
monly than posterior or panuveitis) are reported in <1% of
patients taking ICIs [13, 15]. There have also been reports
of orbital inflammation, episcleritis, blepharitis, optic nerve
swelling, peripheral ulcerative keratitis and Vogt-Koyanagi-
Harada picture with localized serous retinal detachment
[100102]. Patients prescribed ICIs should be advised to
alert the clinician to new onset of blurred vision, floaters,
flashing lights, changes in color vision, eye redness, photo-
phobia or light sensitivity, visual distortion and visual field
changes, scotomas, tender eyes or pain on eye movement,
eyelid swelling or proptosis or double vision. Patient coun-
seling is crucial to ensure that early signs and symptoms
are recognized in a timely manner.
Diagnostic evaluation
Although prompt ophthalmologic referral is important
in ALL cases of visual complaints, certain tests can be
performed by the oncologist in the office. These include
examination for visual acuity, which can be done using
an eye chart on a smart phone with the patient wearing
reading glasses for near vision or glasses for distant vi-
sion, as necessary; color vision; red reflex; pupils (equal,
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 24 of 28
round, reactive), including testing for an afferent pupillary
defect, which can indicate optic nerve or extensive retinal
disease; and penlight inspection of the anterior part of the
eye. Direct ophthalmoscopy to examine the optic nerve
and retina is unlikely to be useful for diagnosis of ret-
inal or optic nerve issues when performed by a non-
ophthalmology-trained physician. Ocular irAEs may be
asymmetric so it is important to examine each eye separ-
ately. Ocular irAEs are frequently accompanied by irAEs
in other systems, especially colitis, so broader systems
inquiry is helpful.
When to refer
Complaints of red, painful, dry or irritated eyes, or visual
disturbance in a patient taking an ICI should alert the
clinician to the need for immediate ophthalmological re-
ferral for diagnosis, classification and management, which
can be difficult for the oncologist since different ocular
pathologies and grades may present with similar symp-
toms and detailed ophthalmological evaluation needs to
be performed by an ophthalmologist, including a slit lamp
exam and dilated fundus exam. Sometimes grade 2 or 3
severity irAEs may only present with asymptomatic or
mild changes in vision, and time to ophthalmology access
can vary depending on the setting (academic versus com-
munity hospital). Clinical suspicion and prompt referral
are therefore essential. Starting systemic or topical treat-
ment with corticosteroids prior to conducting an eye
exam should be avoided unless systemic steroids are indi-
cated for a concurrent, non-ophthalmological toxicity,
since it may worsen ocular conditions that are due to in-
fection (e.g., herpetic keratitis/uveitis) or may mask accur-
ate diagnosis and severity grading when the patient is
examined by an ophthalmologist. Urgent referral is war-
ranted for any grade 3 or 4 irAEs, but even patients with
grade 1 or 2 toxicities should undergo full ophthalmo-
logical evaluation, proper grading, work up and treatment
evaluation by an ophthalmologist within a few days.
Puffy eyelids may indicate early preseptal cellulitis,
which requires systemic antibiotic treatment. Warning
signs (eyelid swelling with pain and erythema, proptosis,
pain with eye movements, movement restriction/diplopia,
vision changes) should prompt urgent ophthalmology
referral.
Conclusions
As the number of patients treated with checkpoint inhibi-
tors grows, and the volume of real-world data increases,
the etiology and characterization of immunotherapy-
related toxicities will become clearer, and management
more targeted and effective. Since adverse events may
occur late, even after terminating active treatment, and
there is a potential for long-term chronic complications,
constant vigilance and early recognition and treatment of
immune-related adverse events is important. Until
prospective clinical data are available, the consensus
recommendations provided here, on the diagnosis and
management of immune checkpoint inhibitor-related ad-
verse events, will hopefully serve as a starting point to
help clinicians provide timely and effective management
of immune-related toxicities in their patients with cancer.
Additional file
Additional file 1: Table S1. Recommended management of uncommon
dermatologic immune-related adverse events. (DOCX 24 kb)
Abbreviations
2-D echo: Two-dimensional echocardiogram/echocardiography;
6MWT: 6 min walk test; AACR: American Association for Cancer Research;
ACCC: Association of Community Cancer Centers; ACPA: Anti-citrullinated
protein antibodies; ACTH: Adrenocorticotropic hormone; ADCC: Antibody-
dependent cell-mediated cytotoxicity; ADL: Activities of daily living;
ALT: Alanine aminotransferase; ANA: Antinuclear antibody; Anti-CCP: Cyclic
citrullinated peptide antibody; Anti-RF: Anti-rheumatoid factor (anti-RF);
Anti-TNF: Anti-tumor necrosis factor; ASCO: American Society of Clinical
Oncology; AST: Aspartate aminotransferase; ATG: Anti-thymocyte globulin;
BAL: Bronchoalveolar lavage; BID: Two times daily; BNP: B-type natriuretic
peptide; BSA: Body surface area; CBC: Complete blood count; CK: Creatine
kinase; CMP: Complete metabolic panel; CMV: Cytomegalovirus; CNS: Central
Nervous System; COP: Cryptogenic organizing pneumonia; COPD: Chronic
obstructive pulmonary disease; CRP: C-reactive protein; CT: Computed
tomography; CTCAE: Common Terminology Criteria for Adverse Events;
CTLA-4: Cytotoxic T lymphocyte-antigen-4; DIC: Disseminated intravascular
coagulation; DLCO: Diffusing capacity of the lungs for carbon monoxide;
DMARDS: Disease modifying anti-rheumatic drugs; DRESS: Drug rash with
eosinophilia and systemic symptoms; EBUS: Endobronchial ultrasound;
ECG: Electrocardiogram; ESR: Erythrocyte sedimentation rate; FDA: U.S. Food
and Drug Administration; FDG-PET: Fluorodeoxyglucose positron emission
tomography; FNA: Fine needle aspiration; FOBT: Fecal occult blood test;
FreeT4: Free thyroxine; FSH: Follicle-stimulating hormone; FVC: Forced vital
capacity; GAD65: Glutamic acid decarboxylase; GCA: Giant cell arteritis;
GI: Gastrointestinal; HbA1c: Glycated hemoglobin; HBcAb: Hepatitis B core
antibody; HBsAb: Hepatitis B surface antibody; HBsAg: Hepatitis B surface
antigen; HCAb: Hepatitis C antibody; Hgb: Hemoglobin; HIV: Human
immunodeficiency virus; HP: Hypersensitivity pneumonitis; HRT: Hormone
Replacement Therapy; HSV: Herpes simplex virus; IBD: Inflammatory bowel
disease; ICIs: Immune checkpoint inhibitors; ICU: Intensive care unit;
IF: Immunofluorescence; IgE: Immunoglobulin E; IgG1: Immunoglobulin G1;
IgG4: Immunoglobulin G4; irAEs: Immune-related adverse events;
IVIG: Intravenous immunoglobulin; LH: Luteinizing hormone; LLN: Lower limit
of Normal; mAbs: Monoclonal antibodies; MCP: Metacarpophalangeal;
MedDRA: Medical Dictionary for Regulatory Activities; MRI: Magnetic
resonance imaging; NCCN: National Comprehensive Cancer Network;
NCI: National Cancer Institute; NIH: National Institutes of Health; NSCLC:
Non-small cell lung carcinoma; NSIP: Nonspecific interstitial pneumonitis; NT
pro-BNP: N-terminal pro B-type natriuretic peptide; ONS: Oncology Nursing
Society; PASI: psoriasis area severity index; PCR: Polymerase chain reaction;
PD-1: Programmed cell death protein-1; PD-L1: Programmed cell death-
ligand 1; PF: Pulmonary fibrosis; PFTs: Pulmonary function tests; PIP: Proximal
interphalangeal; PMR: Polymyalgia rheumatic; PRES: Posterior Reversible
Encephalopathy Syndrome; QID: Four times daily; RA: Rheumatoid arthritis;
RAIUS: Radioactive iodine uptake scan; SITC: Society for Immunotherapy of
Cancer; SJS/TEN: Stevens-Johnson Syndrome/toxic epidermal necrolysis;
SLE: Systemic lupus erythematosus; T1DM: Type I Diabetes; T3: Triiodothyronine;
TBBx: Transbronchial lung biopsy; Tc: Technetium; Th17.1: T helper 17 cells;
TLC: Total lung capacity; TNFi: Tumor necrosis factor inhibitor; TPO: Thyroid
peroxidase; TRAb: Thyroid-stimulating hormone receptor antibody;
TSH: Thyroid-stimulating hormone; TSI: Thyroid-stimulating immunoglobulin;
UIP: Usual interstitial pneumonitis; ULN: Upper Limit of Normal; UVB: Short wave
ultraviolet B; VZV: Varicella zoster virus; Zn-T8: Zinc transporter 8
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 25 of 28
Acknowledgements
The workshop on managing toxicities associated with immune checkpoint
inhibitors was made possible by sponsorship from AstraZeneca Pharmaceuticals,
LP; Bristol-Myers Squibb, and Merck & Co, Inc. Contributions to the content of this
white paper from representatives from these companies represent the clinical
expertise of the individual authors and not the position of the corporation.
Medical writing support for the development of this white paper was provided
by Esther Berkowitz at the Society for Immunotherapy of Cancer; no funding
support was provided for this purpose.
** The following individuals were contributing authors for the Society for
Immunotherapy of Cancer Toxicity Management Working Group:
Jeff Anderson, Bristol-Myers Squibb Company, New York, NY.
Deborah Arrindell, Amgen, Inc., Thousand Oaks, CA.
Stephanie Andrews, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
Joan Ballesteros, Vivia Biotech S.L., Tres Cantos, Spain.
Janie Boyer, AstraZeneca, Gaithersburg, MD.
Daniel Chen, Genentech, Inc., San Francisco, CA.
David Chonzi, Kite Pharma, Los Angeles, CA.
Ion Cotarla, AstraZeneca, Gaithersburg, MD.
Renato Cunha, National Cancer Institute, Bethesda, MD.
Marianne Davies, Yale Cancer Center, New Haven, CT.
Michelle Dawson, AstraZeneca, Gaithersburg, MD
.
Adam Dicker, Thomas Jefferson University, Philadelphia, PA.
Lisa Eifler, Prometheus Therapeutics & Diagnostics, San Diego, CA.
Andrew Ferguson, Gritstone Oncology, Inc., Emeryville, CA.
Cristiano Ferlini, F. Hoffmann La Roche Ltd., New York, NY.
Stanley Frankel, Celgene Corporation, Summit, NJ.
William Go, Kite Pharma, Los Angeles, CA.
Celestine Gochett, KentuckyOne Health, Louisville, KY.
Jenna Goldberg, Janssen Pharmaceuticals, Inc., New York, NY.
Priscila Goncalves, HIV and AIDS Malignancy Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD.
Trishna Goswami, AstraZeneca, Gaithersburg, MD.
Nancy Gregory, Prometheus Therapeutics & Diagnostics, San Diego, CA.
James L. Gulley, National Cancer Institute, Bethesda, MD.
Vinny Hayreh, AstraZeneca, Gaithersburg, MD.
Nicole Helie, Johns Hopkins Department of Neurology and Neurosurgery
Clinical Trials, Baltimore, MD.
William Holmes, AstraZeneca, Gaithersburg, MD.
Jer-Yuan Hsu, NGM Biopharmaceuticals, Inc., San Francisco, CA.
Ramy Ibrahim, Parker Institute for Cancer Immunotherapy, San Francisco, CA.
Cecilia Larocca, Dana Farber Cancer Institute/Brigham and Womens Hospital,
Boston, MA.
Kimberly Lehman, Bristol-Myers Squibb Company, New York, NY.
Sergio Ley-Acosta, Genentech, Inc., San Francisco, CA.
Olivier Lambotte, Assistance Publique Hôpitaux de Paris, France.
Jason Luke, University of Chicago, Chicago, IL.
Joan McClure, National Comprehensive Cancer Network, Fort Washington, PA.
Elisabete Michelon, Pfizer Inc., New York, NY.
Mary Nakamura, University of California, San Francisco, CA.
Kiran Patel, Janssen Pharmaceuticals, Inc., New York, NY.
Bilal Piperdi, Merck & Co., Kenilworth, NJ.
Zeshaan Rasheed, AstraZeneca, Gaithersburg, MD.
Dan Reshef, Bristol-Myers Squibb Company, New York, NY.
Joanne Riemer, Johns Hopkins Hospital, Baltimore, MD.
Caroline Robert, Institut Gustave Roussy, Villejuif, France.
Makan Sarkeshik, AstraZeneca, Gaithersburg, MD.
Ann Saylors, Bristol-Myers Squibb Company, New York, NY.
Judy Schreiber, AstraZeneca, Gaithersburg, MD.
Kim Shafer-Weaver, AstraZeneca, Gaithersburg, MD.
William Sharfman, Johns Hopkins Medicine, Baltimore, MD.
Elad Sharon, Cancer Therapy Evaluation Program, National Cancer Institute,
Bethesda, MD.
Richard Sherry, Surgery Branch, Center for Cancer Research, National Cancer
Institute, Bethesda, MD.
Cyndy Simonson, (Un)Common Sense Solutions, Raleigh, NC.
Cherry Thomas, Jounce Therapeutics, Inc., Cambridge, MA.
John A. Thompson, University of Washington/Fred Hutchinson Cancer
Research Center, Seattle, WA.
Elizabeth Trehu, Jounce Therapeutics, Inc., Cambridge, MA.
Dina Tresnan, Pfizer Inc., Groton, CT.
Michelle Turner, Bristol-Myers Squibb Company, New York, NY.
Darshan Wariabharaj, Janssen Pharmaceuticals, Inc., New York, NY.
Ian Waxman, Bristol-Myers Squibb Company, New York, NY.
Lauren Wood, National Cancer Institute, Bethesda, MD.
Lin Zhang, EMD Serono, Inc., Rockland, MA.
Pan Zheng, Childrens National Medical Center, Washington D.C.
Michelle Dawson participated in this workshop while employed by Bristol
Myers Squibb Company, New York, NY, but has since moved to AstraZeneca,
Gaithersburg, MD.
Authorscontributions
IP, AD, KA, COB, CB, RD, LH, SK, MEL, NRL, DL, CO, VS, RS, AWS, DS, MESA, YW,
KW, HLK, MSE participated in the drafting of these guidelines and
contributed to the writing of the manuscript as well asread and approved
the final manuscript. IP, HLK, and MSE organized and lead the workshop
where the guidelines were developed.
Authors information
Dr. Abdallah participated in this workshop while employed by AstraZeneca,
Gaithersburg, MD but has since moved to Merck & Co., Inc.
Dr. Lenihan participated in this workshop while employed at Vanderbilt
University Medical Center, Nashville, TN, but has since moved to Washington
University in St Louis, St Louis, MO.
Competing interests
AF declared that he is an employee of Gritstone Oncology, Inc. BP declared
that he is an employee and shareholder of Merck & Co., Inc. CS declared that
she is a member of Genentech, Inc. Tecentriq Speakers Bureau. CR declared
that she received personal fees through service on the advisory boards at
Bristol-Myers Squibb Co., GlaxoSmithKline Pharmaceuticals Ltd., Novartis
International AG, Amgen, Inc., Merck & Co., Inc., and F. Hoffmann-La Roche,
Ltd. DC declared that he was employed by Genentech, Inc., until June 2016.
DJL declared that he has received personal compensation as a consultant for
F. Hoffmann-La Roche, Ltd., Bristol-Myers Squibb Co., and Amgen, Inc., and
research support from Takeda Pharmaceuticals U.S.A., Inc. DT declared that
she is an employee and shareholder of Pfizer, Inc. DW declared that he has
been an employee and shareholder of Janssen Research & Development,
LLC, from May 2016, to present, and an employee of Bayer Healthcare
Pharmaceuticals, Inc., from June 2012, to May 2016. IP declared that he
received consulting fees from Amgen, Inc., and F. Hoffmann-La Roche, Ltd. JR
declared that she is a research nurse at Johns Hopkins University and works with
patients receiving IO agents from multiple sponsors and investigator-initiated
studies; JR has also participated in Institute for Clinical Immuno-Oncology
Immunotherapy Workshops, has participated in reviewing educational
materials developed by AstraZeneca committee and an advisory board
meeting sponsored by Merck EMD. JS declared that she is an employee of
AstraZeneca Pharmaceuticals. KA declared that he was an employee of
AstraZeneca Pharmaceuticals until May 2015, is currently an employee and
shareholder of Merck & Co., Inc., and is a shareholder of Sanofi. KS-W declared
that she is an employee of AstraZeneca Pharmaceuticals. MD declared that she
has a financial relationship with Speakers Bureau: AstraZeneca Pharmaceuticals;
Genentech, Inc.; Merck & Co., Inc.; Bristol-Myers Squibb Co. ML declared that he
has received personal fees from Quintiles Inc., Janssen Research & Development,
LLC, AstraZeneca Pharmaceuticals, Genentech, Inc., Foamix Pharmaceuticals Inc.,
Infinity Pharmaceuticals, Adgero Biopharmaceuticals Holdings, Inc., Bristol-Myers
Squibb Co., and Berg LLC. MS declared that he is an employee of AstraZeneca
Pharmaceuticals. MS-A declared that she participated in the Bristol-Myers Squibb
Co Advisory Board. OL declared that he has financial relationships with Bristol-
Myers Squibb Co, MSD (Merck & Co., Inc.) and Janssen Research & Development,
LLC. RD Declared that she receives personal fees from serving on the advisory
board at Bristol-Myers Squibb Co. SA declared that she has a financial relationship
with Genentech, Inc. Speakers Bureau. SL declared that he was an employee of
Janssen Research & Development, LLC until January 2016, and is currently an
employee of Genentech, Inc. VH declared that she is an employee of AstraZeneca
Pharmaceuticals. WS declared that he received consulting fees and general
funding from Merck & Co., Inc., Bristol-Myers Squibb Co, and Novartis International
AG. ZR declared that he is an employee of AstraZeneca Pharmaceuticals. All
remaining authors declared no competing interests.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 26 of 28
Author details
1
Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
2
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Merck
& Co., Inc., Upper Gwynedd, PA, USA.
4
Johns Hopkins University, Baltimore,
MD, USA.
5
Bristol-Myers Squibb Company, New York, NY, USA.
6
Memorial
Sloan Kettering Cancer Center, New York, NY, USA.
7
Dana Farber/Brigham
and Womens Cancer Center, Boston, MA, USA.
8
Washington University in St
Louis, St Louis, MO, USA.
9
Indiana University, Indianapolis, IN, USA.
10
University of Chicago, Chicago, IL, USA.
11
Oncology Nursing Society,
Pittsburgh, PA, USA.
12
Massachusetts General Hospital, Boston, MA, USA.
Received: 26 September 2017 Accepted: 6 November 2017
References
1. Hoos A. Development of immuno-oncology drugs - from CTLA4 to PD1 to
the next generations. Nat Rev Drug Discov. 2016;15(4):23547.
2. Papaioannou NE, et al. Harnessing the immune system to improve cancer
therapy. Ann Transl Med. 2016;4(14):261.
3. Administration, U.S.F.a.D. Drugs@FDA: FDA approved drug products. 2017
June 19th, 2017]; Available from: https://www.accessdata.fda.gov/scripts/
cder/daf/index.cfm.
4. Company, B.-M.S. Ipilimumab (Yervoy) Highlights of Prescribing Information.
2017 3/2017 [cited 2017 June 19th, 2017]; Available from: https://www.
accessdata.fda.gov/drugsatfda_docs/label/2015/125377s073lbl.pdf.
5. Company, B.-M.S. Nivolumab (Opdivo) Highlights of Prescribing Information.
2017 4/2017 [cited 2017 June 19th, 2017]; Available from: https://
packageinserts.bms.com/pi/pi_opdivo.pdf.
6. Merck & Co., I. Pembrolizumab (Keytruda) Highlights of Prescribing
Information. 2017 5/2017 June 19th, 2017]; Available from: https://www.
merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.
7. Genentech, I. Atezolizumab (Tecentriq) Highlights of Prescribing
Information. 2017 4/2017 [cited 2017 June 19th, 2017]; Available from:
https://www.gene.com/download/pdf/tecentriq_prescribing.pdf.
8. LP, A.P. Durvalumab (Imfinzi) Highlights of Prescribing Information. 2017 4/
2017 [cited 2017 June 19th, 2017]; Available from: https://www.accessdata.
fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf.
9. EMD Serono, I. Avelumab (Bavencio) Highlights of Prescribing Information.
2017 5/2017 [cited 2017 June 19th, 2017]; Available from: https://www.
bavencio.com/en_US/document/Prescribing-Information.pdf.
10. Eggermont AM, et al. Prolonged survival in stage III melanoma with
Ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):184555.
11. Bertrand A, et al. Immune related adverse events associated with anti-CTLA-
4 antibodies: systematic review and meta-analysis. BMC Med. 2015;13:211.
12. Maughan BL, et al. Incidence of immune-related adverse events with
program death Receptor-1- and program death Receptor-1 ligand-directed
therapies in genitourinary cancers. Front Oncol. 2017;7:56.
13. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on
management of immune-related toxicities. Transl Lung Cancer Res. 2015;4(5):56075.
14. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1
antibody in cancer. N Engl J Med. 2012;366(26):244354.
15. Kumar V, et al. Current diagnosis and Management of Immune Related
Adverse Events (irAEs) induced by immune checkpoint inhibitor therapy.
Front Pharmacol. 2017;8:49.
16. Ascierto PA, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in
patients with unresectable or metastatic melanoma: a randomised,
double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18(5):61122.
17. Tarhini, A.A., et al., A phase III randomized study of adjuvant ipilimumab
(3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk
melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the
ipilimumab arms.Journal of Clinical Oncology, 2017. 35(15_suppl): p. 95009500.
18. Lin Z, et al. PD-1 antibody monotherapy for malignant melanoma: a
systematic review and meta-analysis. PLoS One. 2016;11(8):e0160485.
19. Collins LK, et al. Cutaneous adverse effects of the immune checkpoint
inhibitors. Curr Probl Cancer. 2017;41(2):1258.
20. Hua C, et al. Association of Vitiligo with Tumor Response in patients with metastatic
melanoma treated with Pembrolizumab. JAMA Dermatol. 2016;152(1):4551.
21. Prior, L.M., et al., Toxicities in immunotherapy: Can they predict response? J
Clin Oncol, 2016. 34(15_suppl): p. e14534-e14534.
22. Johnson DB, et al. Fulminant myocarditis with combination immune
checkpoint blockade. N Engl J Med. 2016;375(18):174955.
23. Kwon ED, et al. Ipilimumab versus placebo after radiotherapy in patients
with metastatic castration-resistant prostate cancer that had progressed
after docetaxel chemotherapy (CA184-043): a multicentre, randomised,
double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):70012.
24. Hodi FS, et al. Improved survival with ipilimumab in patients with
metastatic melanoma. N Engl J Med. 2010;363(8):71123.
25. Ernstoff, M., et al., Challenges faced when identifying patients for
combination immunotherapy. Future Oncology, 2017;153(11):1162-1165.
26. Pennock GK, Chow LQ. The evolving role of immune checkpoint inhibitors
in cancer treatment. Oncologist. 2015;20(7):81222.
27. Luke JJ, Ott PA. PD-1 pathway inhibitors: the next generation of
immunotherapy for advanced melanoma. Oncotarget. 2015;6(6):347992.
28. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint
inhibitors. Cancer Treat Rev. 2016;44:5160.
29. Derosa L R.B., Mezquita L, Naltet C, Enot D, Fidelle M, Goubet A-G, Soria JC,
Massard C, Goldwasser F, Zitvogel L, Brosseau S, Escudier BJ, Loriot Y,
Zalcman G, Besse B, Albiges L., Antibiotics prescription to decrease
progression-free survival (PFS) and overall survival (OS) in patients with
advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors. J
Clin Oncol. 2017;35(Supplement 6S; abstract 462).
30. Kaderbhai C, et al. Antibiotic use does not appear to influence response to
Nivolumab. Anticancer Res. 2017;37(6):3195200.
31. Weber JS, et al. Safety profile of Nivolumab monotherapy: a pooled analysis
of patients with advanced melanoma. J Clin Oncol. 2017;35(7):78592.
32. Horvat TZ, et al. Immune-related adverse events, need for systemic
immunosuppression, and effects on survival and time to treatment failure in
patients with melanoma treated with Ipilimumab at memorial Sloan Kettering
cancer center. J Clin Oncol. 2015;33(28):31938.
33. SERVICES., U.S.D.O.H.A.H., Common Terminology Criteria for Adverse Events
(CTCAE) Version 4.03. 2010. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_
2010-06-14_QuickReference_8.5x11.pdf.
34. Woodworth T, et al. Standardizing assessment and reporting of adverse
effects in rheumatology clinical trials II: the rheumatology common toxicity
criteria v.2.0. J Rheumatol. 2007;34(6):140114.
35. Immunotherapy, F.o.C.R.P.I.f.C. Streamlined Toxicity Management Guide_
Working Draft_322.2017. 2017.
36. Belum VR, et al. Characterisation and management of dermatologic adverse
events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:1225.
37. Rivera N, et al. Hair Repigmentation during immunotherapy treatment with
an anti-programmed cell death 1 and anti-programmed cell death ligand 1
agent for lung cancer. JAMA Dermatol. 2017;153(11):1162-1165.
38. Weber JS, Kähler KC, Hauschild A. Management of Immune-Related Adverse
Events and Kinetics of response with Ipilimumab. J Clin Oncol. 2012;30(21):26917.
39. Weber JS. Practical management of immune-related adverse events from
immune checkpoint protein antibodies for the oncologist. Am Soc Clin Oncol
Educ Book. 2012:1747. https://meetinglibrary.asco.org/record/66896/edbook.
40. Larkin J, et al. Combined Nivolumab and Ipilimumab or monotherapy in
untreated melanoma. N Engl J Med. 2015;373(1):2334.
41. Weinstock C, et al. U.S. Food and Drug Administration approval summary:
Atezolizumab for metastatic non-small cell lung cancer. Clin Cancer Res. 2017;
23(16):4534-453.
42. Cramer P, Bresalier RS. Gastrointestinal and hepatic complications of
immune checkpoint inhibitors. Curr Gastroenterol Rep. 2017;19(1):3.
43. Oble DA, et al. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and
immunohistochemical analysis. Am J Surg Pathol. 2008;32(8):11307.
44. Gupta A, et al. Systematic review: colitis associated with anti-CTLA-4
therapy. Aliment Pharmacol Ther. 2015;42(4):40617.
45. Berman D, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by
ipilimumab results in dysregulation of gastrointestinal immunity in patients
with advanced melanoma. Cancer Immun. 2010;10:11.
46. Chen JH, et al. Histopathologic features of colitis due to immunotherapy
with anti-PD-1 antibodies. Am J Surg Pathol. 2017;41(5):64354.
47. Weber J, et al. A randomized, double-blind, placebo-controlled, phase II
study comparing the tolerability and efficacy of ipilimumab administered
with or without prophylactic budesonide in patients with unresectable
stage III or IV melanoma. Clin Cancer Res. 2009;15(17):55918.
48. Pompili M, et al. Tumor necrosis factor-alpha inhibitors and chronic hepatitis C:
a comprehensive literature review. World J Gastroenterol. 2013;19(44):786773.
49. Lin MV, et al. The influence of anti-TNF therapy on the course of chronic
hepatitis C virus infection in patients with inflammatory bowel disease. Dig
Dis Sci. 2013;58(4):114956.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 27 of 28
50. Kim KW, et al. Ipilimumab-associated colitis: CT findings. AJR Am J
Roentgenol. 2013;200(5):W46874.
51. Jain A, et al. Colonic ulcerations may predict steroid-refractory course in
patients with ipilimumab-mediated enterocolitis. World J Gastroenterol.
2017;23(11):20238.
52. Gonzalez RS, et al. PD-1 inhibitor gastroenterocolitis: case series and appraisal
of immunomodulatory gastroenterocolitis. Histopathology. 2017;70(4):55867.
53. Kim KW, et al. Ipilimumab associated hepatitis: imaging and
clinicopathologic findings. Investig New Drugs. 2013;31(4):10717.
54. Johncilla M, et al. Ipilimumab-associated hepatitis: Clinicopathologic
characterization in a series of 11 cases. Am J Surg Pathol. 2015;39(8):107584.
55. Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint
inhibitor-induced hepatitis. Am J Surg Pathol. 2017;41(1):1347.
56. Marthey L, et al. Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies
induces an inflammatory bowel disease. J Crohns Colitis. 2016;10(4):395401.
57. Ryder M, et al. Endocrine-related adverse events following ipilimumab in
patients with advanced melanoma: a comprehensive retrospective review
from a single institution. Endocr Relat Cancer. 2014;21(2):37181.
58. Weber JS, et al. Toxicities of immunotherapy for the practitioner. J Clin
Oncol. 2015;33(18):20929.
59. Dadu R, Zobniw C, Diab A. Managing adverse events with immune
checkpoint agents. Cancer J. 2016;22(2):1219.
60. Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment,
and biologic insights. Pituitary. 2016;19(1):8292.
61. Marie Joelle Pitteloud RD, Cabanillas ME, Shah K, Mimi I-Nan H, Habra MA,
Waguespack SG, et al. Hypophysitis in the Age of Cancer Immunotherapy:
Experience in a Large Cancer Center, in Endocrine Societys 97th Annual
Meeting and Expo. San Diego: CA; 2015.
62. Corsello SM, et al. Endocrine side effects induced by immune checkpoint
inhibitors. J Clin Endocrinol Metab. 2013;98(4):136175.
63. Blansfield JA, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage
can induce autoimmune hypophysitis in patients with metastatic
melanoma and renal cancer. J Immunother. 2005;28(6):5938.
64. Byun DJ, et al. Cancer immunotherapy - immune checkpoint blockade and
associated endocrinopathies. Nat Rev Endocrinol. 2017;13(4):195207.
65. Johnson DB, et al. Survivorship in immune therapy: assessing chronic immune
toxicities, health outcomes, and functional status among long-term Ipilimumab
survivors at a single referral center. Cancer Immunol Res. 2015;3(5):4649.
66. Weber JS, et al. Management of Adverse Events Following Treatment with
Anti-Programmed Death-1 agents. Oncologist. 2016;21(10):123040.
67. Chamberlain JJ, et al. Diagnosis and Management of Diabetes: synopsis of
the 2016 American Diabetes Association standards of medical Care in
Diabetes. Ann Intern Med. 2016;164(8):54252.
68. Naidoo J, et al. Pneumonitis in patients treated with anti-programmed
Death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):70917.
69. Khunger M, et al. Incidence of pneumonitis with use of PD-1 and PD-L1
inhibitors in non-small cell lung cancer: a systematic review and meta-
analysis of trials. Chest. 2017;152(2):271-281.
70. Wu J, et al. PD-1 inhibitors increase the incidence and risk of pneumonitis
in cancer patients in a dose-independent manner: a meta-analysis. Sci Rep.
2017;7:44173.
71. Nishino M, et al. Incidence of programmed cell death 1 inhibitor-related
pneumonitis in patients with advanced cancer: a systematic review and
meta-analysis. JAMA Oncol. 2016;2(12):160716.
72. Delaunay M, et al. Immune-checkpoint inhibitors associated with interstitial
lung disease in cancer patients. Eur Respir J. 2017;50(2). doi:10.1183/
13993003.00050-2017.
73. Lomax AJ, et al. Immunotherapy-induced sarcoidosis in patients with
melanoma treated with PD-1 checkpoint inhibitors: case series and
immunophenotypic analysis. Int J Rheum Dis. 2017;20(9):1277-1285.
74. Vogel WV, et al. Ipilimumab-induced sarcoidosis in a patient with metastatic
melanoma undergoing complete remission. J Clin Oncol. 2012;30(2):e7e10.
75. Andersen R, et al. Late development of splenic sarcoidosis-like lesions in a
patient with metastatic melanoma and long-lasting clinical response to
ipilimumab. Oncoimmunology. 2014;3(8):e954506.
76. Suarez-Almazor ME, et al. Review: immune-related adverse events with use
of checkpoint inhibitors for immunotherapy of cancer. Arthritis Rheumatol.
2017;69(4):68799.
77. Cappelli LC, et al. Rheumatic and musculoskeletal immune-related adverse
events due to immune checkpoint inhibitors: a systematic review of the
literature. Arthritis Care Res (Hoboken). 2016;69(11):1751-1763.
78. Naidoo J, et al. Inflammatory arthritis: a newly recognized adverse event of
immune checkpoint blockade. Oncologist. 2017;22(6):62730.
79. Weber JS, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in
ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31(34):43118.
80. Postow M W.J. Toxicities associated with checkpoint inhibitor
immunotherapy. UpToDate 2017 [cited 2017 June 22nd, 2017]; available
from: https://www.uptodate.com/contents/toxicities-associated-with-
checkpoint-inhibitor-immunotherapy.
81. Gibney GT, et al. Safety, correlative markers, and clinical results of adjuvant
nivolumab in combination with vaccine in resected high-risk metastatic
melanoma. Clin Cancer Res. 2015;21(4):71220.
82. Momtaz P, et al. Safety of infusing Ipilimumab over 30 minutes. J Clin
Oncol. 2015;33(30):34548.
83. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of
potential cardiac problems. Clin Cancer Res. 2008;14(1):1424.
84. Lurz P, et al. Diagnostic performance of CMR imaging compared with EMB in
patients with suspected myocarditis. JACC Cardiovas c Imaging. 2012;5(5):51324.
85. Heinzerling L, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking
immunotherapy. J Immunother Cancer. 2016;4:50.
86. Shiuan E, et al. Thrombocytopenia in patients with melanoma receiving
immune checkpoint inhibitor therapy. J Immunother Cancer. 2017;5:8.
87. Hopkins AM, et al. Predicting response and toxicity to immune checkpoint
inhibitors using routinely available blood and clinical markers. Br J Cancer.
2017;117(7):91320.
88. Michot JM, et al. Immune-related adverse events with immune checkpoint
blockade: a comprehensive review. Eur J Cancer. 2016;54:13948.
89. Cortazar FB, et al. Clinicopathological features of acute kidney injury
associated with immune checkpoint inhibitors. Kidney Int. 2016;90(3):63847.
90. Wanchoo R, et al. Adverse renal effects of immune checkpoint inhibitors: a
narrative review. Am J Nephrol. 2017;45(2):1609.
91. Escandon J, et al. Interstitial nephritis in melanoma patients secondary to
PD-1 checkpoint inhibitor. J Immunother Cancer. 2017;5:3.
92. Boutros C, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies
alone and in combination. Nat Rev Clin Oncol. 2016;13(8):47386.
93. Rizvi NA, et al. Nivolumab in combination with platinum-based doublet
chemotherapy for first-line treatment of advanced nonsmall-cell lung
cancer. J Clin Oncol. 2016;34(25):296979.
94. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus
nephritis. N Engl J Med. 2009;361(2):2112.
95. Izzedine H, et al. Kidney injuries related to ipilimumab. Investig New Drugs.
2014;32(4):76973.
96. Thajudeen B, et al. Ipilimumab granulomatous interstitial nephritis. Am J
Ther. 2015;22(3):e847.
97. Kaufman HL, et al. Avelumab in patients with chemotherapy-refractory
metastatic Merkel cell carcinoma: a multicentre, single-group, open-label,
phase 2 trial. Lancet Oncol. 2016;17(10):137485.
98. Cuzzubbo S, et al. Neurological adverse events associated with immune
checkpoint inhibitors: review of the literature. Eur J Cancer. 2017;73:18.
99. Hottinger AF. Neurologic complications of immune checkpoint inhibitors.
Curr Opin Neurol. 2016;29(6):80612.
100. Bricout M, et al. Vogt-Koyanagi-Harada-like syndrome complicating Pembrolizumab
treatment for metastatic melanoma. J Immunother. 2017;40(2):7782.
101. Matsuo T, Yamasaki O. Vogt-Koyanagi-Harada disease-like posterior uveitis in
the course of nivolumab (anti-PD-1 antibody), interposed by vemurafenib
(BRAF inhibitor), for metastatic cutaneous malignant melanoma. Clin Case
Rep. 2017;5(5):694700.
102. Papavasileiou E, et al. Ipilimumab-induced ocular and orbital inflammationa
case series and review of the literature. Ocul Immunol Inflamm. 2016;24(2):1406.
103. Pages C, et al. Ipilimumab-induced acute severe colitis treated by infliximab.
Melanoma Res. 2013;23(3):22730.
104. Tripathi A, et al. Programmed cell death-1 pathway inhibitors in genitourinary
malignancies: specific side-effects and their management. Curr Opin Urol.
2016;26(6):54855.
Puzanov et al. Journal for ImmunoTherapy of Cancer (2017) 5:95 Page 28 of 28
... Second, immune-mediated toxicity was considered. Colitis is the second most commonly reported AE with ICI administration, and the symptoms typically develop from 6 to 8 weeks from the start of treatment; median onset of transaminase elevation is approximately 6-14 weeks after starting ICIs [33]. The pathogenesis of ICI-induced hepatitis is not well understood. ...
Article
Full-text available
Patients with cancer have a higher risk of severe COVID-19, and expert consensus advocates for COVID-19 vaccination in this population. Some cases of autoimmune hepatitis have been described after the administration of COVID-19 vaccine in the people in apparently good health. Immune checkpoint inhibitors (ICIs) are responsible for a wide spectrum of immune-related adverse events (irAEs). This article reports a case of hepatitis and colitis in a 52-year-old woman who was undergoing immunotherapy and was HBV positive 10 days after receiving the first Pfizer-BioNTech COVID-19 vaccine dose. Because both ICIs and the COVID-19 vaccines stimulate the immune response, the authors hypothesize that these vaccines may increase the incidence of irAEs during ICI treatment. There is a complex interplay between the immune-mediated reaction triggered by the vaccination and PD-L1 co-administration.
... A consensus from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group suggested that cardiac troponins screening should be performed in the first 12 weeks of ICI treatment (45). The assessment of creatine phosphokinase (CPK) may be useful because myocarditis is an inflammatory disease and may be associated with myositis (46), but this less sensitive marker may not rise significantly (47). ...
Article
Full-text available
The development of various antitumor drugs has significantly improved the survival of patients with cancer. Many first-line chemotherapy drugs are cytotoxic and the cardiotoxicity is one of the most significant effects that could leads to poor prognosis and decreased survival rate. Cancer treatment include traditional anthracycline drugs, as well as some new targeted drugs such as trastuzumab and ICIs. These drugs may directly or indirectly cause cardiovascular injury through different mechanisms, and lead to increasing the risk of cardiovascular disease or accelerating the development of cardiovascular disease. Cardiotoxicity is clinically manifested by arrhythmia, decreased cardiac function, or even sudden death. The cardiotoxicity caused by traditional chemotherapy drugs such as anthracyclines are significantly known. The cardiotoxicity of some new antitumor drugs such like immune checkpoint inhibitors (ICIs) is also relatively clear and requiring further observation and verification. This review is focused on major three drugs with relatively high incidence of cardiotoxicity and poor prognosis and intended to provide an update on the clinical complications and outcomes of these drugs, and we innovatively summarize the monitoring status of survivors using these drugs and discuss the biomarkers and non-invasive imaging features to identify early cardiotoxicity. Finally, we summarize the prevention that decreasing antitumor drugs-induced cardiotoxicity.
... Pre-ICI therapies, in which steroids were given before the start of the ICI, were found to have little to no effect on the rates of irAEs in studies [157]. Anti-TNF-alpha drugs have shown success in treating uveitis, colitis, and hepatitis in steroid-resistant irAEs [158]. Additional research has found that cyclophosphamide and mycophenolate for pneumonitis, and methotrexate and hydroxychloroquine for arthritis, are effective for steroid-resistant irAEs [159]. ...
Article
Full-text available
Immunotherapy, which stimulates the body’s immune system, has received a considera- ble amount of press in recent years because of its powerful benefits. Cancer immunotherapy has shown long-term results in patients with advanced disease that are not seen with traditional chem- otherapy. Immune checkpoint inhibitors, cytokines like interleukin 2 (IL-2) and interferon-alpha (IFN), and the cancer vaccine sipuleucel-T have all been licensed and approved by the FDA for the treatment of various cancers. These immunotherapy treatments boost anticancer responses by stim- ulating the immune system. As a result, they have the potential to cause serious, even fatal, inflam- matory and immune-related side effects in one or more organs. Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell therapy are two immunotherapy treatments that are increasingly being used to treat cancer. Following their widespread usage in the clinic, a wave of immune-related adverse events (irAEs) impacting virtually every system has raised concerns about their unpredictability and randomness. Despite the fact that the majority of adverse effects are minimal and should be addressed with prudence, the risk of life-threatening complications ex- ists. Although most adverse events are small and should be treated with caution, the risk of life- threatening toxicities should not be underestimated, especially given the subtle and unusual indi- cations that make early detection even more difficult. Treatment for these issues is difficult and necessitates a multidisciplinary approach involving not only oncologists but also other internal medicine doctors to guarantee quick diagnosis and treatment. This study’s purpose is to give a fun- damental overview of immunotherapy and cancer-related side effect management strategies.
... Similar to common drug-induced liver injury, grading hepatic irAEs are based on the Common Terminology Criteria for Adverse Events. Management recommendations of hepatic irAEs are referred to a colitis model (Table 4) [162][163][164]. ...