Resumption of Immune Checkpoint Inhibitor
Therapy After Immune-Mediated Colitis
Hamzah Abu-Sbeih, MD1; Faisal S. Ali, MD2; Abdul Rafeh Naqash, MD3; Dwight H. Owen, MD, MS4; Sandipkumar Patel, MD4;
Gregory A. Otterson, MD4; Kari Kendra, MD, PhD4; Biagio Ricciuti, MD5; Rita Chiari, MD, PhD5; Andrea De Giglio, MD5;
Joseph Sleiman, MD6; Pauline Funchain, MD6; Beatriz Wills, MD7; Jiajia Zhang, MD, MPH8; Jarushka Naidoo, MBBCh8;
Jessica Philpott, MD9; Jianjun Gao, MD, PhD1; Sumit K. Subudhi, MD, PhD1; and Yinghong Wang, MD, PhD1
PURPOSE Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea
and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption.
METHODS This retrospective multicenter study examined patients who resumed ICI therapy after improvement of
IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses
assessed the association of clinical covariates and IMDC recurrence.
RESULTS Of the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent,
and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years
(interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days
(IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and
32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for
recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI
resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients
who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45;
95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immuno-
suppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC
symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower
after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11
to 0.81; P = .019).
CONCLUSION One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Re-
currence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-4.
J Clin Oncol 37:2738-2745. © 2019 by American Society of Clinical Oncology
Creative Commons Attribution Non-Commercial No Derivatives 4.0 License
ASSOCIATED
CONTENT INTRODUCTION and pancreatitis.3 Development of irAEs is indicative
See accompanying Immune checkpoint inhibitors (ICIs) have revolution- of an augmented immune response, which is asso-
Oncology Grand ized cancer therapy and have been the focus of in- ciated with prolonged overall survival, and should be
Rounds on page 2714
tensive clinical and basic research in recent years. ICIs considered a surrogate marker for positive response
Listen to the podcast 4-6
augment antitumor immune response by blocking cy- to ICI therapy. We previously reported longer overallby Dr Oh at survival among patients who develop immune-
http://ascopubs.org/ totoxic T-cell lymphocyte-4 (CTLA-4) or programmed
jco/podcasts mediated diarrhea and colitis (IMDC).
5,6 However,
cell death 1 or ligand-1 (PD-1/L1) or both, resulting in
Appendix considerable controversy exists with regard to thesignificant response rates in a subset of malignancies.1
Author affiliations impact of irAEs on survival because some investigators
and support Currently, studies are assessing ICI safety and efficacy have not found a similar impact.7,8
information (if in an increasing array of solid tumors as well as he-
applicable) appear matologic malignancies.2 IMDC can be severe enough to cause colon perforation
at the end of this and death if not treated appropriately.9 Therefore,
article. The toxicity profile of ICIs is distinct from those of timely and precise management of IMDC is critical
Accepted on May 6, other cancer therapies and falls under the umbrella for favorable outcomes.10-12 Current treatment guide-
2019 and published at term immune-related adverse events (irAEs) because lines recommend holding ICI therapy in patients with
jco.org on June 4, of their autoimmune nature.1 In theory, irAEs can
2019: DOI https://doi. grade 2 or higher IMDC and initiating corticosteroid
org/10.1200/JCO.19. affect any organ system and frequently manifest as therapy.
13-15 A subset of these patients may resume
00320 dermatitis, diarrhea, colitis, pneumonitis, hepatitis, ICI therapy, particularly anti–PD-1/L1, when IMDC
2738 Volume 37, Issue 30
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original report abstract
Immune Checkpoint Inhibitor Therapy Resumption After Colitis
symptoms subside to grade 1. Furthermore, it may be Common Terminology Criteria of Adverse Events (version
possible to hold ICI therapy temporarily (in cases of 5.0) was used to grade IMDC at its peak severity.20 The
cancer progression) or indefinitely (in cases of cancer duration of IMDC symptoms was measured as the cu-
remission) because the optimum number of doses of mulative number of days from IMDC onset until symptom
anti–PD-1/L1 remains unknown. However, a paucity of resolution.
evidence exists on the safety profile of ICI resumption in Clinical Outcomes
patients who stopped treatment because of the de-
velopment of an irAE. The primary end point of this study was recurrence of IMDC
after resuming ICI therapy. Time from IMDC occurrence to
One large-scale study that assessed the safety of resuming ICI restart, type of ICI restarted, reason to restart ICI, time
anti–PD-1 therapy included 80 patients previously treated from ICI restart to IMDC recurrence (if any), peak grade of
with a combination anti–CTLA-4 and anti–PD-1 ICI regimen the recurrent IMDC, and treatment required for the re-
who developed a treatment-limiting irAE.16 Although the current IMDC were recorded.
findings were encouraging and have added to the current
body of evidence, they did not address patients who were Statistical Analyses
previously treated with anti–PD-1/L1 or anti–CTLA-4 ther- The distributions of continuous variables were summarized
apy as a single agent and then resumed the same or using medians and interquartile ranges (IQRs). The dis-
a different ICI agent. Because IMDC frequently requires tributions of categorical variables were summarized using
interruption of ICI treatment, the current study aimed to frequencies and percentages. Categorical variables were
identify the incidence and characteristics of and risk factors compared between groups by Fisher’s exact and x2 tests.
for recurrent IMDC after resumption of ICI therapy in pa- Continuous variables were compared by Wilcoxon rank
tients in whom ICI treatment was withheld because sum test. To assess the risk factors for IMDC recurrence, we
of IMDC. performed a univariable followed by a multivariable logistic
regression. Clinical characteristics that were significant in
METHODS the univariable analysis or were relevant to clinical practice
(ie, type of ICI resumed) were included in the multivariable
Patient Cohort model. Requirement for infliximab or vedolizumab was
This retrospective multicenter study was approved by the not added to the multivariable analysis because its ef-
institutional review boards of the participating institutions fect is included as part of immunosuppression. Hosmer-
(Appendix Table A1, online only). Included patients were Lemeshow test was used to measure the goodness of fit
18 years of age or older who received an ICI and developed of the included variables in the multivariable logistic re-
IMDC between January 2010 and November 2018 and gression model and revealed P = .22, which indicates
then resumed ICI therapy after it was suspended because a good fit of the variables in the multivariable logistic model.
of IMDC onset. Patients were identified from pharmacy and In addition, collinearity was evaluated using the variance
institutional databases. inflation factor, which assesses how much the variance of
Clinical Data an estimated regression coefficient increases if the pre-
dictors are correlated. The highest variance inflation factor
Demographic information, medical and oncologic history, for our model was 1.66, which indicates that there was no
and data related to ICI therapy and IMDC were extracted multicollinearity. All statistical tests were two-sided. P# .05
from the medical record of each identified patient. was considered statistically significant. Statistical analyses
Comorbid conditions included in the Charlson comorbidity were carried out using SAS 9.4 (SAS Institute, Cary, NC)
index score were recorded.17 Cancer stage was determined and SPSS version 24.0 (IBM Corporation, Chicago, IL)
according to the seventh edition of the American Joint software.
Committee on Cancer Staging System but was not recorded
for patients with hematologic malignancies because of the RESULTS
intricate staging systems used.
Patient Selection
ICI and IMDC Information Among 550 patients who had IMDC, we identified 167
The recorded information that pertained to ICI included (30%) who received ICI treatment after the onset of IMDC;
type, number of infusions, and duration of treatment. In patient demographic and clinical characteristics are
addition, we documented the reason for resuming ICI listed in Table 1. The median age was 60 years (IQR, 50-69
therapy after IMDC as cancer progression, resolution of years). Initial ICI therapy was a PD-1/L1 inhibitor in 79
irAE, or maintenance therapy. Cancer progression was patients (47%), a CTLA-4 inhibitor in 47 (28%), and
assessed as reported in the medical chart by the treating a combination in 41 (25%). Melanoma was the most
oncologist and radiologist according to the immune- common malignancy type in this cohort (54%) followed
modified Response Evaluation Criteria in Solid Tumors by non–small-cell lung cancer (16%) and genitourinary
(imRECIST) and immune RECIST (iRECIST).18,19 The cancer (10%).
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Abu-Sbeih et al
TABLE 1. General Characteristics of the Patient Cohort Initial IMDC and Non-GI irAEs
Characteristic Patients, No. (%)
The median duration of initial IMDC symptoms was 12 days
No. of patients 167 (IQR, 5-28 days). Seventy-five patients had an endoscopic
Median age, years (IQR) 60 (50-69) evaluation. A majority of the patients who developed IMDC
Male sex 100 (60) required immunosuppression with a corticosteroid (113;
White race 156 (93) 68%); among them, 24 patients (14%) required treatment
escalation to addition of infliximab or vedolizumab. Non-GI
Comorbid conditions present 92 (55)
irAEs were reported in 72 patients (43%) and involved skin
Cancer type (n = 22), liver (n = 11), endocrine organs (n = 29), lung
Melanoma 90 (54) (n = 9), or other sites (n = 19).
Non–small-cell lung cancer 27 (16)
ICI Resumption and IMDC Recurrence
Genitourinary 17 (10)
ICI therapy was re-initiated because of cancer progression
Other solid* 26 (16)
or relapse in 48 patients (29%), whereas 119 (71%) either
Hematologic 7 (4) continued therapy as maintenance therapy with good re-
Cancer stage (n = 160) sponse to ICI or resumed therapy after irAE resolution. The
III 21 (13) median duration from initial IMDC to ICI resumption was
IV 139 (87) 49 days (IQR, 23-136 days). On resuming ICI therapy,
Median duration of initial ICI therapy, days (IQR) 59 (25-126) a majority of patients received an anti–PD-1/L1 agent (135;
81%), whereas 32 (19%) received an anti–CTLA-4 agent
Median no. of initial ICI infusions (IQR) 3 (2-7) (Table 2). Overall, IMDC recurred in 57 patients (34%) after
Initial ICI type a median of 53 days (IQR, 22-138 days) after ICI re-
Anti–CTLA-4 47 (28) sumption. Of the 57 patients who experienced IMDC re-
Anti–PD-1/L1 79 (47) currence, the majority experienced grade 2 diarrhea (40;
Combination 41 (25) 70%) and grade 1 colitis (30; 54%). Most IMDC re-
currences required corticosteroid therapy (46; 81%).
Highest grade of initial diarrhea (n = 165)†
Seven patients (12%) required treatment escalation to ad-
1 46 (28) dition of infliximab or vedolizumab for the recurrent
2 57 (35) IMDC.
3-4 62 (38) Of the 43 patients (32%) who experienced IMDC recurrence
Highest grade of initial colitis (n = 138)† after resuming anti–PD-1/L1 therapy, 26 (37%) initially re-
1 41 (30) ceived an anti–PD-1/L1 agent, and 17 (27%) initially re-
2 52 (38) ceived an anti–CTLA-4 agent. Of the 14 patients (44%) who
experienced IMDC recurrence after resuming anti–CTLA-4
3-4 45 (33)
therapy, seven (88%) initially received an anti–PD-1/L1
Median duration of initial IMDC symptoms, days (IQR) 12 (5-28) agent, and seven (29%) initially received an anti–CTLA-4
Hospitalizations 78 (47) agent (Fig 1). Monthly nivolumabwas the re-initiated ICI type
Treatment of initial IMDC in 44 patients; among them, 10 (23%) had IMDC re-
Supportive care only 54 (32) currence. Of the 113 patients who received immunosup-
pressive therapy for initial IMDC, 47 (42%) had recurrent
Corticosteroid 113 (68)
IMDC. Of the seven patients who had IMDC grade 4 initially
Infliximab or vedolizumab add-on 24 (14) and resumed ICI therapy (anti–CTLA-4 in two patients and
Non-GI adverse events of initial ICI therapy 72 (43) anti–PD-1/L1 in five), four (57%) had IMDC recurrence.
Reason to re-initiate ICI therapy In patients who resumed anti–CTLA-4 therapy, IMDC re-
Disease progression 48 (29) currence was reported after a median of 26 days (IQR, 2-43
Continue therapy after IMDC resolution 119 (71) days) and occurred significantly earlier than recurrence
after anti–PD-1/L1 resumption (median, 79 days; IQR, 27-
Abbreviations: CTLA-4, cytotoxic T-cell lymphocyte-4; ICI, immune checkpoint
141 days; P = .024; Table 2). No differences were observed
inhibitor; IMDC, immune-mediated diarrhea and colitis; IQR, interquartile range;
PD-1/L1, programmed cell death 1 or ligand 1. in the severity of IMDC recurrence between the two groups.
*Other solid cancer types included head and neck, Meckel cell, endocrine, The recurrence of IMDC was more severe (P , .001) and
hepatobiliary, gynecologic, breast, and GI malignancies. required more intensive immunosuppressive therapy (P ,
†Grades of diarrhea and colitis were determined by Common Terminology .001) in patients who received immunosuppressive therapy
Criteria for Adverse Events (version 5.0). for the initial event than in those who did not (Table 3).
2740 © 2019 by American Society of Clinical Oncology Volume 37, Issue 30
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Immune Checkpoint Inhibitor Therapy Resumption After Colitis
TABLE 2. Characteristics of Recurrent IMDC on the Basis of Resumed ICI Therapy
Resumed ICI Therapy, No. (%)
Characteristic Anti–CTLA-4 Monotherapy Anti–PD-1/L1 Monotherapy P
No. of patients 32 135
Recurrence of IMDC symptoms 14 (44) 43 (32) .302
Time from ICI resumption to IMDC recurrence, days (IQR) 26 (2-43) 79 (27-141) .024
Treatment of IMDC recurrence .307
Symptomatic only 3 (9) 8 (6)
Corticosteroid 8 (25) 31 (23)
Infliximab or vedolizumab add-on 3 (9) 4 (3)
Grade of recurrent diarrhea* .497
1 2 (6) 9 (7)
2 11 (34) 29 (22)
3-4 1 (3) 5 (4)
Grade of recurrent colitis* .388
1 7 (22) 23 (17)
2-3 6 (19) 20 (15)
Abbreviations: CTLA-4, cytotoxic T-cell lymphocyte-4; ICI, immune checkpoint inhibitor; IMDC, immune-mediated diarrhea and colitis; IQR,
interquartile range; PD-1/L1, programmed cell death 1 or ligand 1.
*Grades of diarrhea and colitis were determined by Common Terminology Criteria for Adverse Events (version 5.0).
Risk Factors for IMDC Recurrence higher grades of IMDC (P = .007), requirement for inflix-
On univariable analysis (Table 4), initial use of anti–PD-1/L1 imab or vedolizumab at initial IMDC (P = .035), and longer
therapy (P = .034), cancer stage III (P = .049), requirement duration of initial IMDC symptoms (P = .035) were asso-
for immunosuppressive therapy at initial IMDC (P = .003), ciated with an increased likelihood of IMDC recurrence
after ICI resumption. Inflammation identified by endoscopy
in the initial IMDC episode tended to increase the risk of
Patients with IMDC IMDC recurrence (P = .069).
(N = 167)
Multivariable logistic regression analysis (Table 5) revealed
that the initial use of anti–CTLA-4 was associated with
a lower risk of IMDC recurrence upon ICI resumption (P =
.002). Regardless of initial therapy, however, the resumption
CTLA-4 PD-1/L1
(n = 88) (n = 79) of anti–PD-1/L1 therapy, as opposed to anti–CTLA-4 therapy,
was associated with a lower risk of IMDC recurrence (P =
.019). In addition, patients who required immunosuppres-
ICI
resumption sive therapy for initial IMDC were more likely to experience
IMDC recurrence after the resumption of ICI therapy
(P = .019). Likewise, a long duration of IMDC symptoms in
the initial episode was associated with a higher risk of IMDC
CTLA-4 PD-1/L1 CTLA-4 PD-1/L1 recurrence (P = .031).
(n = 24) (n = 64) (n = 8) (n = 71)
DISCUSSION
IMDC This multicenter study aimed to evaluate and characterize
recurrence
the recurrence of IMDC after the resumption of ICI therapy
after a first occurrence of IMDC. Our approach of studying
(n = 7; (n = 17; (n = 7; (n = 26; recurrent ICI toxicity differs from previously published
29%) 27%) 88%) 37%) studies in that our cohort comprised patients with different
types of cancer who received different types of ICI therapy.
FIG 1. Recurrence of immune-mediated diarrhea and colitis (IMDC) Although such an approach limits in-depth analysis of
after immune checkpoint inhibitor (ICI) resumption. CTLA-4, cytotoxic oncologic outcomes, it allows for generalizable data about
T-cell lymphocyte-4; PD-1/L1, programmed cell death 1 or ligand 1. the toxicity profile of ICIs irrespective of cancer type. We
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Abu-Sbeih et al
TABLE 3. Characteristics of Recurrent IMDC for Patients Who Required finding agrees with the limited body of evidence about the
Immunosuppressive Therapy for Initial IMDC resumption of ICIs. In the study by Pollack et al,16 which
No comprised 80 patients with melanoma previously treated
Immunosuppression, Immunosuppression, with a combination ICI regimen who developed a clinically
Characteristic No. (%) No. (%) P
significant irAE and were rechallenged with anti–PD-1
No. of patients 47 10 therapy, the recurrence of grade 3/4 colitis was 3%. In
Time from ICI resumption 51 (20-130) 59 (25-140) .786 another study of eight patients with melanoma who were
to IMDC recurrence, previously treated with anti–PD-1 therapy and rechallenged
days (IQR)
with an anti–PD-1 agent, recurrent grade 1 IMDC was
Treatment of IMDC , .001 reported in one.21 In addition to melanoma, the resumption
recurrence of ICI therapy in patients with non–small-cell lung cancer
Symptomatic only 2 (4) 9 (90) has been reported (two case series and one case
Corticosteroid 39 (83) 0 (0) report).22-24 None of these three studies reported a re-
Infliximab or 6 (13) 1 (10) currence of grade 3/4 IMDC. The discrepancy between
vedolizumab add-on these reports and our findings could be the result of the low
Grade of recurrent , .001 rate of high-grade initial IMDC in those reports because we
diarrhea* found that more severe IMDC is a predictor of recurrence.
1 3 (6) 8 (80) In addition, because ICI use has become more widespread
2 38 (81) 2 (20) and practitioners have become more comfortable with irAE
management, ICI rechallenge has broadened.
3-4 6 (13) 0 (0)
Recurrent IMDC in our cohort was generally manageable by
Abbreviations: ICI, immune checkpoint inhibitor; IMDC, immune-mediated established treatment approaches. No serious AEs that led
diarrhea and colitis; IQR, interquartile range. to mortality were identified in this IMDC cohort. By contrast,
*Grades of diarrhea and colitis were determined by Common Terminology Pollack et al16 reported progression of a grade 2 rash as the
Criteria for Adverse Events (version 5.0).
initial event to a grade 3 rash with anti–PD-1 resumption,
which evolved into fatal Stevens-Johnson syndrome.
found the incidence of recurrent IMDC to be lower in Hence, although the severity of IMDC after resumption of
patients who resumed an anti–PD-1/L1 agent than in those ICI therapy seems to be mild, caution should be practiced.
who resumed an anti–CTLA-4 agent. Close monitoring for progression in severity of irAEs should
We found that IMDC after ICI resumption was mostly grade prompt timely management efforts, including adequate
1 to 2 in severity, irrespective of the ICI type resumed. This immunosuppressive therapy as well as ICI discontinuation
TABLE 4. Univariable Logistic Regression Analysis of IMDC Recurrence
Covariate Odds Ratio 95% CI P
Age 1.02 0.99 to 1.04 .187
Male sex 1.55 0.79 to 3.02 .199
Cancer stage III 0.28 0.08 to 0.99 .049
Duration of initial ICI treatment 1.00 0.99 to 1.00 .960
Anti–CTLA-4 initial therapy 0.50 0.26 to 0.95 .034
Resumption of anti–PD-1/L1 therapy 0.62 0.28 to 1.37 .236
Time from ICI stop to resumption 1.00 0.99 to 1.00 .843
Required immunosuppressive therapy initially 3.25 1.49 to 7.9 .003
Required infliximab or vedolizumab initially 2.57 1.07 to 6.19 .035
Grade of initial diarrhea*
2 2.39 0.97 to 5.93 .058
3-4 3.39 1.39 to 8.19 .007
Duration of initial IMDC symptoms 1.01 1.00 to 1.02 .035
Other non-GI irAEs 0.65 0.34 to 1.24 .190
Inflammation on endoscopy of the initial IMDC 2.61 0.93 to 7.31 .069
Abbreviations: CTLA-4, cytotoxic T-cell lymphocyte-4; ICI, immune checkpoint inhibitor; IMDC, immune-mediated diarrhea and colitis; irAE,
immune-related adverse event; PD-1/L1, programmed cell death 1 or ligand 1.
*Grades of diarrhea and colitis were determined by Common Terminology Criteria for Adverse Events (version 5.0).
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Immune Checkpoint Inhibitor Therapy Resumption After Colitis
TABLE 5. Multivariable Logistic Regression Analysis of IMDC Recurrence Our findings reveal that even upon resumption of anti–
Covariate Odds Ratio 95% CI P CTLA-4 therapy, the risk of severe IMDC seems to be
Initial ICI type acceptable. Although resumption of anti–PD-1/L1 ther-
Anti–CTLA-4 Reference apy is more desirable when limitation of the toxicity profile
is among the major goals of care, the presumed toxicity
Anti–PD-1/L1 3.45 1.59 to 7.69 .002
risk associated with anti–CTLA-4 therapy should not
ICI type resumed prevent clinicians from considering resumption of these
Anti–CTLA-4 Reference drugs when this may be the only resort for prolonging
Anti–PD-1/L1 0.30 0.11 to 0.81 .019 survival. In addition, patients who develop irAEs tend to
Grade of initial diarrhea* have high rates of response to ICI therapy, which are
sustained and may obviate ICI resumption.1,28-30 Hence,
1 Reference
the decision to resume ICI therapy in patients with an
2 1.19 0.37 to 3.80 .775 ongoing durable response can be difficult, and more
3-4 2.19 0.66 to 7.29 .202 studies are needed to outline the subset of patients who
Required immunosuppressive 3.22 1.08 to 9.62 .019 will benefit from ICI resumption. Careful delineation of
therapy initially goals of care should be discussed with patients before
Duration of initial IMDC symptoms 1.01 1.00 to 1.03 .031 treatment planning because this will help in making
decisions that are in line with each patient’s wishes and
Abbreviations: CTLA-4, cytotoxic T-cell lymphocyte-4; ICI, immune checkpoint optimize the subsequent quality of life of already de-
inhibitor; IMDC, immune-mediated diarrhea and colitis; PD-1/L1, programmed cell
bilitated patients with cancer.1
death 1 or ligand 1.
*Grades of diarrhea and colitis were determined by Common Terminology In addition to the inherent fallacies of a retrospective
Criteria for Adverse Events (version 5.0). design, the patient cohort was heterogeneous because
our aim was to characterize the toxicity profile of ICI
if deemed appropriate. In the setting of IMDC, colon biopsy of resumption. One limitation of such an approach is the
mucosal ulcerations and nonulcerative inflammation, as well inability to perform cancer-specific survival analyses.
as seemingly normal mucosal areas, on colonoscopy can Second, no predetermined criteria were used to decide
help to identify active inflammation and guide the duration of which patients could resume ICI therapy, and decisions
immunosuppressive therapy.11,12,25 relied on the clinical judgment of the individual treating
Our findings on multivariable analysis that anti–CTLA-4 physician. Third, because our cohort only consisted of
therapy resumption was associated with an increased risk patients who resumed ICI therapy, we did not account for
of IMDC recurrence, whereas prior anti–CTLA-4 use was patients who were deemed not to be candidates for ICI
a predictor of low risk of IMDC recurrence, hint at the relative resumption for any reason, which reflects an inherent
significance of prior and resumed ICI therapy and their selection bias and limits the generalizability of our findings.
impact on toxicity recurrence. The clinical implication of Fourth, because the focus of our study was IMDC, de-
this observation should be taken into consideration when termination of the characteristics and recurrence of non-GI
planning ICI resumption in patients in whom previous ICI irAEs was not attempted. Fifth, practice standards could
therapy failed or had to be terminated altogether because of have been different at the various institutions of this study
AEs. Similarly, Pollack et al16 concluded that patients with and could have had an impact on our data. Finally, because
colitis and hypophysitis can safely resume anti–PD-1 ICI of the limited sample size, multiple subgroup analyses may
therapy. In real-life settings, however, treatment decisions have been underpowered.
are made on a per-patient basis, depending on comorbid In conclusion, one third of patients who resumed ICI
conditions and cancer therapy options. therapy after IMDC experienced recurrent IMDC that
Timely recognition and treatment of IMDC are critical to was mostly mild and could be managed adequately with
sustain ICI therapy.31 To achieve this goal, the use of immunosuppressive therapy. The lower risk of recurrent
potent nonsteroidal immunosuppressive therapy, such IMDC upon resumption of ICI is intriguing and suggests
as infliximab or vedolizumab, may be considered, al- that ICI resumption in many patients is at least safe,
though the long-term effect of such drugs on cancer especially anti–PD-1/L1 therapy. Caution should be
outcomes is not yet known.10,26 A new IMDC treatment practiced before resuming ICI therapy, especially in
strategy with great promise and no known immunosup- patients with severe initial IMDC. Future prospective
pressive effect is fecal microbiota transplantation, which studies with larger patient cohorts and predetermined
was found by our group to be a novel treatment of criteria for resumption should validate the safety and
immunosuppression-refractory IMDC.27 efficacy of ICI resumption in the setting of IMDC.
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Abu-Sbeih et al
AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
1The University of Texas MD Anderson Cancer Center, Houston, TX AND DATA AVAILABILITY STATEMENT
2Presence Saint Joseph Hospital, Chicago, IL Disclosures provided by the authors and data availability statement (if
3East Carolina University, Greenville, NC applicable) are available with this article at DOI https://doi.org/10.1200/
4The Ohio State University, Columbus, OH JCO.19.00320.
5University of Perugia, Perugia, Italy
6Cleveland Clinic Foundation, Cleveland, OH AUTHOR CONTRIBUTIONS
7Johns Hopkins University, Baltimore, MD Conception and design: Hamzah Abu-Sbeih, Yinghong Wang
8Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Provision of study material or patients: Abdul Rafeh Naqash, Sandipkumar
University and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Patel, Gregory A. Otterson, Kari Kendra, Rita Chiari, Jarushka Naidoo,
Baltimore, MD Yinghong Wang
9Cleveland Clinic, Cleveland, OH
Collection and assembly of data: Hamzah Abu-Sbeih, Abdul Rafeh
Naqash, Dwight H. Owen, Sandipkumar Patel, Gregory A. Otterson, Kari
CORRESPONDING AUTHOR Kendra, Biagio Ricciuti, Rita Chiari, Andrea De Giglio, Joseph Sleiman,
Yinghong Wang, MD, PhD, Department of Gastroenterology, Hepatology Pauline Funchain, Beatriz Wills, Jiajia Zhang, Jarushka Naidoo
and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Data analysis and interpretation: Hamzah Abu-Sbeih, Faisal S. Ali,
Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ywang59@ Sandipkumar Patel, Kari Kendra, Joseph Sleiman, Jiajia Zhang, Jarushka
mdanderson.org. Naidoo, Jessica Philpott, Jianjun Gao, Sumit K. Subudhi, YinghongWang
Manuscript writing: All authors
PRIOR PRESENTATION Final approval of manuscript: All authors
Presented at the Society for Immunotherapy of Cancer 2018, Accountable for all aspects of the work: All authors
Washington, DC, November 7-11, 2018.
ACKNOWLEDGMENT
Medical editing of this article was provided by the Department of
Scientific Publications at MD Anderson Cancer Center. The biostatistical
analysis was performed by Dr. Wei Qiao in the Department of Biostatistics
at MD Anderson Cancer Center.
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Abu-Sbeih et al
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held
unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about
ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Dwight H. Owen Jarushka Naidoo
Consulting or Advisory Role: L&M Policy Research, AstraZeneca Honoraria: Bristol-Myers Squibb, AstraZeneca, MedImmune
Research Funding: Bristol-Myers Squibb (Inst), Palobiofarma (Inst), Merck Consulting or Advisory Role: Bristol-Myers Squibb, AstraZeneca, MedImmune,
Sharp & Dohme (Inst), Genentech (Inst), Roche (Inst) Roche, Genentech
Travel, Accommodations, Expenses: AstraZeneca Research Funding: Merck (Inst), Calithera Biosciences (Inst), AstraZeneca
(Inst)
Gregory A. Otterson Travel, Accommodations, Expenses: Bristol-Myers Squibb, AstraZeneca,
Consulting or Advisory Role: Novartis, Takeda Pharmaceuticals, Novocure MedImmune
Research Funding: Genentech (Inst), Roche (Inst), Bristol-Myers Squibb (Inst),
Novartis (Inst), Merck (Inst), AstraZeneca (Inst), Celgene (Inst) Jianjun Gao
Consulting or Advisory Role: AstraZeneca, ARMO BioSciences, CRISPR
Kari Kendra Therapeutics, Jounce Therapeutics, Nektar, Polaris, Pfizer
Research Funding: Novartis (Inst), Bristol-Myers Squibb (Inst), GlaxoSmithKline Travel, Accommodations, Expenses: AstraZeneca
(Inst), Karyopharm Therapeutics (Inst), Merck (Inst)
Sumit K. Subudhi
Rita Chiari Stock and Other Ownership Interests: Apricity Health
Speakers’ Bureau: Takeda Pharmaceuticals Honoraria: Compugen, Apricity Health, Janssen Pharmaceuticals, Dendreon
Consulting or Advisory Role: Valeant, Dendreon, Apricity Health, Janssen
Pauline Funchain Pharmaceuticals, Polaris
Consulting or Advisory Role: Eisai Travel, Accommodations, Expenses: Janssen Pharmaceuticals, Compugen,
Dendreon
No other potential conflicts of interest were reported.
© 2019 by American Society of Clinical Oncology Volume 37, Issue 30
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Copyright © 2020 American Society of Clinical Oncology. All rights reserved. 
Immune Checkpoint Inhibitor Therapy Resumption After Colitis
APPENDIX
TABLE A1. Included Patients From Each Institution
Institution No. of patients
The University of Texas MD Anderson Cancer Center 116
Ohio State University 19
University of Perugia 18
Cleveland Clinic Foundation 10
Johns Hopkins University 3
East Carolina University 1
Journal of Clinical Oncology
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