Original article 321
Ipilimumab-induced colitis in patients with metastatic melanoma Kara M. De Felicea, Arjun Guptaa, Sagar Rakshita, Sahil Khannaa, Lisa A. Kottschadeb, Heidi D. Finnesb, Konstantinos A. Papadakisa, Edward V. Loftus Jra, Laura E. Raffalsa and Svetomir N. Markovicb Ipilimumab is used for the treatment of metastatic melanoma and is associated with serious immune-related colitis. We aimed to report the clinical features, treatment, and outcomes of patients with ipilimumab-induced colitis. In this retrospective observational study, we identified patients with unresectable melanoma treated with ipilimumab between March 2011 and September 2013. Diarrhea was assessed using the Common Terminology Criteria for Adverse Events, v3.0. Colitis was defined by diarrhea (grade ≥ 2) requiring steroids with or without endoscopic/histologic/radiologic evidence of colitis. A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades), and 23 patients (22%) developed colitis requiring systemic corticosteroid therapy. The median number of ipilimumab doses before onset of diarrhea was 2 (range, 1–4). Six of 23 patients responded to less than 1 mg/kg daily prednisone alone. Fifteen patients required high-dose oral and/or intravenous prednisone (1–2 mg/kg body weight). Six patients had diarrhea refractory to prednisone; five required rescue therapy with budesonide (9–12 mg daily) and one was treated with
Introduction One-third of patients treated with ipilimumab therapy for metastatic melanoma develop ipilimumab-induced colitis [1]. Ipilimumab is a fully human monoclonal antibody (IgG1) that targets cytotoxic T-lymphocyte antigen [2]. The immune dysregulation caused by the neutralization of regulatory cytotoxic T-lymphocyte antigen molecules on T cells and depletion of regulatory T cells has been associated with several immune-related adverse events, seen in ∼ 64% of patients treated with ipilimumab [3,4]. The most common adverse events involve the skin and luminal gastrointestinal tract; however, side effects including drug-induced hepatitis, adrenal insufficiency, hypothyroidism, hypophysitis, and neuropathy are also seen [1,5]. Most of these immune-related adverse events are mild-to-moderate, and are reversible with medical management. Less than 1% of immune-related adverse events have led to death [5]. Ipilimumab-induced colitis is a serious immune-related complication, and may lead to colonic perforation and death if left untreated [1]. Guidelines support treatment 0960-8931 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
infliximab (5 mg/kg, three doses). There was one case of severe diarrhea (grade 3) treated successfully with highdose budesonide (12 mg) monotherapy. Ipilimumabinduced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid-sparing agent, however further studies of its efficacy in this setting are needed. Infliximab should be used in refractory cases to avoid colectomy. Melanoma Res 25:321–327 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Melanoma Research 2015, 25:321–327 Keywords: budesonide, corticosteroids, immune-related adverse events, infliximab a Division of Gastroenterology and Hepatology and bDivision of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence to Svetomir N. Markovic, MD, PhD, Division of Medical Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA Tel: + 1 507 538 0118; fax: + 1 507 284 5045; e-mail: [email protected] Received 3 March 2015 Accepted 31 March 2015
with corticosteroids for moderate-to-severe colitis and infliximab or colectomy for refractory cases [6]. We report our experience describing the management and outcomes of 30 cases of ipilimumab-induced diarrhea.
Methods Study design
We conducted a retrospective observational study of patients with stage III/IV melanoma treated with ipilimumab between March 2011 and September 2013 at Mayo Clinic in Rochester, Minnesota, USA. The study was approved by the Ethics Committee and Institutional Review Board of the Mayo Clinic. Patients were identified using a pharmacy database. Patients who were 18 years of age and older, had a confirmed diagnosis of stage III/IV melanoma, treated with ipilimumab 3 mg/kg body weight every 3 weeks, and followed by the Division of Medical Oncology at Mayo Clinic, were included. Ipilimumab clinical trial patients were excluded. Patients who developed diarrhea within 3 months of ipilimumab therapy were identified. Diarrhea was DOI: 10.1097/CMR.0000000000000165
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
322 Melanoma Research
2015, Vol 25 No 4
assessed using the Common Terminology Criteria for Adverse Events (CTCAE), v3.0, (grade 1, < 4 stools per day; grade 2, 4–6 stools daily, abdominal pain, blood or mucus in the stool; grade 3, > 7 stools daily, severe abdominal pain, ileus, fever, peritoneal signs; and grade 4, life-threatening consequences). For the purpose of this study, colitis was defined by diarrhea (grade ≥ 2) requiring steroid therapy with or without endoscopic, histologic, radiologic evidence of colitis. Baseline characteristics including age, sex, smoking history, stage of melanoma, previous treatments, and ipilimumab therapy were documented. Infectious stool studies, endoscopies, and PET/computed tomography (CT) scans were recorded. Treatment regimen, dose, length of treatment, response, and treatment side effects were documented. There was no standardized treatment protocol used for the management of ipilimumab-induced colitis. Complete response was defined as the absence of diarrhea with bowel habits returning to the patient’s baseline, partial response as a decrease in bowel frequency, and no response as worsening or unchanged diarrhea. Statistical analysis
The baseline demographics and clinical characteristics of patients who developed ipilimumab-induced diarrhea were reported as percentages for categorical variables, mean with SD for continuous variables with normal distribution, and median with range for continuous variables with skewed distribution.
Results Patient characteristics
A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades) (Table 1). The median number of completed ipilimumab doses was 4 (range, 1–4). One patient received concomitant sargramostim. No patients received concomitant chemotherapy. Eight patients (27%) received concomitant radiation therapy, although the abdomen was not within the radiation field in any of the patients. Frequency of ipilimumab-induced diarrhea and colitis
Of the 30 patients who experienced diarrhea, 23 developed colitis (22% of the entire cohort). Eight patients within the ipilimumab cohort had previous exposure to ipilimumab; two of whom developed ipilimumabinduced colitis. The frequency of ipilimumab-induced diarrhea in ipilimumab-naive patients was 29% (28/95) and 22% (21/95) developed colitis. Clinical presentation
Five patients developed grade 1 diarrhea, six patients developed grade 2 diarrhea, and 19 patients developed grade 3 diarrhea (Table 2). The median number of ipilimumab doses completed before the onset of diarrhea was two doses
Table 1 Baseline demographics of patients who developed ipilimumab-induced diarrhea Demographics Median age at start of ipilimumab therapy (years) (range) Male Current smoker Current use of daily NSAIDS Personal history of autoimmune disease Metastatic melanoma Stage IV ECOG status = 0 Previous treatment with systemic chemotherapy Previous treatment with IL-2 Previous ipilimumab treatment Previous ipilimumab-induced diarrhea Treatment Median total number of ipilimumab doses completed [n (range)] Concomitant therapy Chemotherapy Radiation Surgery
N = 30 [n (%)] 63 (39–86) 17 1 6 4
(56) (3) (20) (13)
30 (100) 17/26 (65) (4 missing) 17 (57) 1 (3) 8 (27) 2 (25) 4 (1–4)
0 (0) 8 (27) 0 (0)
ECOG, Eastern Cooperative Oncology Group; IL-2, interleukin-2.
(range, 1–4). The majority (90%) of patients presented with watery stools. Only three patients (10%) had bloody stools; all with grade 3 diarrhea. Fifteen patients (50%) presented with abdominal pain and five patients (17%) were febrile at presentation. Diagnosis
A total of 23 patients (73.3% of the 30 patients with diarrhea) developed grade ≥ 2 diarrhea requiring steroid therapy resulting in a clinical diagnosis of colitis. Of these patients, four underwent CT scan to rule out bowel perforation. Only two of these four patients had radiographic evidence of colitis as demonstrated by colonic thickening on CT scan (Fig. 1b). Thirteen patients had diarrhea at the time of PET/CT performed for melanoma staging. Of these 13 patients, six had radiographic evidence of colitis on PET/CT (Fig. 1a). Stool tests to exclude infectious causes of diarrhea were performed at the onset of diarrhea in 15 patients (50%). None of the patients had an infectious etiology identified at initial presentation. Four patients, all with grade 3 diarrhea, underwent endoscopy, and colitis was evident in all. Endoscopic findings included diffuse erythematous, edematous mucosa with friability, exudate, and multiple superficial and deep ulcerations (Fig. 1c). Extensive colitis was seen in three patients and left-sided colitis in one patient. Histology showed active mild-to-moderate chronic colitis with ulcerations, crypt abscesses, and cryptitis (Fig. 1d). Three patients with endoscopic evidence of mild-tomoderate inflammation had a normal PET/CT, with no evidence of increased colonic uptake. Disease location based on endoscopy and/or radiographic images varied amongst patients [pancolitis (seven); left-sided colitis (two), right-sided colitis (one), and segmental colitis (one)].
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ipilimumab-induced colitis De Felice et al. 323
Table 2
Clinical characteristics and treatment of patients with ipilimumab-induced diarrhea Grade 1 (N = 5a)
Onset of diarrhea after median number of ipilimumab dose [n (range)] Colitis [n (%)] Imaging consistent with colitis [n (%)] Endoscopy consistent with colitis [n (%)] Treatment Low-dose prednisone (< 1 mg/kg) [n (%)] High-dose prednisone oral and/or intravenous (1–2 mg/kg) [n (%)] High-dose budesonide (9–12 mg) [n (%)] Infliximab (5 mg/kg) [n (%)] Median duration of total steroid treatment [days (range)] Median duration of prednisone treatment [days (range)] Median duration of budesonide treatment [days (range)] Median days on total steroids to complete response [days (range)] Median days on budesonide to complete response [days (range)] Complete response to treatment [n (%)] Ipilimumab-induced complications [n (%)] Infectious colitis Colectomy or perforations Hospitalizations for diarrhea Steroid-induced complications [n (%)] Adrenal insufficiency Myopathy Concomitant immune-related adverse events [n (%)] Hepatitis Rash Adrenal insufficiency Hypothyroidism Tumor response to ipilimumab treatment [n (%)] Stable disease Partial response Complete response Progressive disease
1 0 0/1 0/0
Grade 2 (N = 6a)
(1–2) (0) (0) (0)
1 4 1/2 0/0
(0) (0) (0) (0) 0 0 0 0 0 5 (100)
4 0 0 0 11 11
0 0 0 0
(1–3) (67) (50) (0)
(67) (0) (0) (0) (2–79) (2–79) 0 11 (2–74) 0 6 (100)
Grade 3 (N = 19a) 2 19 7/15 4/4
(1–4) (100) (47) (100)
2 15 7 1 80 75 110 58 63 19
(11) (79) (37) (5) (32–175) (32–163) (42–157) (12–120) (13–157) (100)
Total (N = 30a) 2 23 8/18 4/4 6 15 7 1 75 68 110 50 63 30
(1–4) (77) (44) (100) (20) (50) (23) (3) (2–175) (2–163) (42–157) (2–120) (13–157) (100)
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 1 (17)
2 (11) 0 (0) 14 (74)
2 (7) 0 (0) 15 (50)
0/0 (0) 0/0 (0)
1/4 (25) 0/4 (0)
2 (11) 1 (5)
3/23 (13) 1/23 (4)
0 2 0 1
(0) (40) (0) (20)
1 1 0 1
(17) (17) (0) (17)
1 2 2 1
(5) (11) (11) (5)
6 5 2 3
(20) (17) (7) (10)
0 1 1 3
(0) (20) (20) (60)
0 1 0 5
(0) (17) (0) (83)
3 3 0 13
(16) (16) (0) (68)
3 4 1 21
(10) (13) (3) (70)
Grade 1; < 4 stools daily. Grade 2; 4–6 stools daily, abdominal pain, blood/mucous stools. Grade 3; > 7 stools daily, severe abdominal pain, ileus, fever, and peritoneal signs. Grade 4; diarrhea with life-threatening consequences. a Denominator is N unless otherwise stated.
Management and treatment response
All patients (n = 5) with grade 1 diarrhea and two of six patients with grade 2 diarrhea were treated symptomatically with loperamide (2–16 mg daily). The remaining four patients with grade 2 diarrhea improved with oral prednisone monotherapy (< 1 mg/kg, 20–50 mg daily, 2–79 days duration). Two of 19 patients with grade 3 diarrhea improved with oral prednisone monotherapy (< 1 mg/kg, 30–60 mg daily, 32–75 days duration). Fifteen patients with grade 3 diarrhea required high-dose oral prednisone (1–2 mg/kg, 60–200 mg daily, 40–165 days duration). Six of these 15 patients also received intravenous corticosteroids (50–1000 mg methylprednisolone daily, median duration 3 days, range 1–6 days). Of the 23 patients who received prednisone, six (26%) had prednisone-refractory diarrhea. Five patients were given a course of oral delayed-release budesonide (9–12 mg daily) despite failing prednisone, and one patient received infliximab (5 mg/kg, three doses). All patients who received budesonide had a complete response and were able to tolerate a prednisone taper by 5–10 mg weekly (median 57 days, range 26–110 days). The one patient treated with infliximab rescue therapy received three doses (5 mg/kg at 0, 2, and 6 weeks) and
was started on budesonide therapy after the first dose of infliximab. After the start of budesonide therapy, the patient was able to titrate off prednisone 60 mg daily in 26 days. The patient had complete resolution of diarrhea 18 days after the first dose of infliximab. There was a single case of severe diarrhea (grade 3) treated successfully with high-dose budesonide (12 mg) monotherapy tapered over 5 months. The median time of onset of symptoms to treatment was 3 days (range, 0–53 days). Median duration of total steroid treatment was 75 days (range, 2–175 days); including prednisone, 68 days (range, 2–163 days) and budesonide, 110 days (range, 42–157 days). The median time of total steroid therapy to complete response was 50 days (range, 2–120 days). The median time of budesonide therapy to complete response was 63 days (range, 13–157 days). Patients with grade 3 diarrhea required longer duration of total steroid, prednisone, and budesonide therapy and had a longer time to complete response (Table 2). Ipilimumab was continued in many of our patients (19/30, 63%) despite the presence of diarrhea. Ipilimumab was discontinued in six patients because of their underlying diarrhea (all with grade 3 diarrhea) and in three patients due to progression of melanoma. The
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
324 Melanoma Research
2015, Vol 25 No 4
Fig. 1
Ipilimumab-induced colitis. (a) Increased fludeoxyglucose (18F) uptake in large intestine suggestive of ipilimumab-induced colitis on PET/CT. (b) Diffuse ipilimumab-colitis as marked by thickening of the entire colon on CT enterography. (c) Ipilimumab-induced colitis on colonoscopy, with edema, loss of vascular pattern, increased granularity, and ulcerations. (d) Moderate active chronic colitis without granulomas, shortened crypts, cryptitis, and crypt abscesses on colon biopsy. CT, computed tomography.
other two patients developed diarrhea after completion of their ipilimumab cycle (four doses) and did not proceed with a second cycle. All patients (any diarrhea grade) had complete resolution of diarrhea symptoms with medical therapy (antidiarrheals, corticosteroid or infliximab) and/or discontinuing ipilimumab.
There were a total of 15 hospitalizations and four emergency department visits for diarrhea. No patient required intensive care unit management. All hospitalized patients received intravenous fluid and electrolyte replacement and one patient required packed red blood cell transfusions due to anemia. Two patients received empiric systemic antibiotics.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ipilimumab-induced colitis De Felice et al. 325
No patients required total parenteral nutrition. There were no colonic perforations nor need for colectomy. The majority of patients had progression of their metastatic melanoma at the end of ipilimumab therapy irrespective of the grade of ipilimumab-induced diarrhea. Adverse events
Two patients developed superimposed infectious colitis (Clostridium difficile and Campylobacter jejuni) and were treated successfully with antibiotics. There were no deaths related to ipilimumab-induced colitis. Steroidinduced side effects and concomitant immune-related adverse events are summarized in Table 2. Restarting ipilimumab
Only three patients with ipilimumab-induced diarrhea (two with grade 3 and one with grade 1) were rechallenged with a second cycle of ipilimumab. One patient was started prophylactically on 12 mg of budesonide before and 1 month after ipilimumab therapy and never developed ipilimumab-induced diarrhea. One patient developed severe ipilimumab-induced colitis requiring hospitalization and intravenous steroids. Another patient is currently undergoing another ipilimumab cycle with no diarrhea to date after one dose.
Discussion Ipilimumab-induced colitis is a serious immune-related adverse event that warrants early recognition and aggressive medical therapy. It can be successfully managed with systemic corticosteroids, high-dose budesonide, and infliximab in refractory cases. Colectomy should be used as a last resort. Similar to other reports in the literature, we noted a 29% overall frequency of diarrhea despite previous treatment with ipilimumab. Patients in our cohort were more likely to have colitis (22 vs. 8%).[4,5] The higher incidence of colitis in our study is most likely explained by our definition of colitis, which differs from other studies. We used a clinical diagnosis of colitis, compared with the CTCAE v3.0, which requires endoscopic or radiologic evidence of colitis. We found an inconsistent correlation between endoscopic and radiologic evidence of colitis in symptomatic patients. The literature also reports normal endoscopic evaluations with histologic findings consistent with ipilimumab-induced colitis [7]. Therefore, we believe that in the proper clinical setting, one can use the severity of clinical symptoms with endoscopic and histologic evidence of colitis to help guide treatment. Only half of our patients had stool studies done to rule out infectious colitis. Two patients developed superimposed infectious colitis. This finding highlights the need for a standardized practice guideline for the management of this patient cohort, which should always include stool studies to exclude infectious causes of
colitis. The endoscopic and histologic findings are similar to inflammatory bowel disease; however, there were no key distinguishing features. Diffuse inflammation was seen in a subset of our cohort, and a similar diffuse colitis has been described in the literature [8]. Nonspecific histopathologic findings showing acute and chronic inflammation have been reported, and we observed similar histopathologic findings [9]. In our cohort, only four patients underwent endoscopic evaluation (all four in consultation with gastroenterology). Endoscopic evaluation should be reserved for those patients with persistent grade 1 and moderate-to-severe diarrhea (grade ≥ 2). Biopsies should be performed to exclude cytomegalovirus colitis. Half of our patients required high doses of prednisone (1–2 mg/kg oral and/or intravenous) for the treatment of ipilimumab-induced colitis. There is a theoretical concern that the use of corticosteroids to manage immunerelated adverse events may dampen the immune-driven efficacy of ipilimumab. Although this has not been demonstrated clinically, published studies are small and further investigation is warranted [10,11]. The use of long-term corticosteroids has been associated with many side effects, and has been shown to increase mortality and the risk of severe infections in patients with Crohn’s disease [12]. In our study, the use of prednisone was associated with steroid-induced side effects in 17% of patients, including three patients who required long-term prednisone therapy for secondary adrenal insufficiency. Six patients had diarrhea refractory to prednisone of whom five required rescue therapy with high-dose oral budesonide (9–12 mg daily). Budesonide therapy was associated with longer overall treatment duration, but was safer with fewer corticosteroid-induced side effects compared with long-term high-dose prednisone. Theoretically, higher doses of budesonide, 12 mg daily, may be more effective in the treatment of colitis as more drug is delivered to the distal colon. Budesonide, 9 mg daily, has been suggested as a treatment for mild-tomoderate (grade 1–2) ipilimumab-associated colitis [6, 13]. In contrast, in a double-blind, randomized phase II controlled trial of ipilimumab with or without prophylactic budesonide (9 mg daily), those treated with prophylactic budesonide did not show a decreased rate of grade ≥ 2 diarrhea compared with placebo. Therefore, budesonide has not been recommended to be used as prophylaxis [14]. However, it has not been studied for treatment of ipilimumab-induced colitis. Infliximab has been used for steroid-refractory severe (grade 3–4) diarrhea in patients with ipilimumab-induced colitis [13,15]. In our study, only one patient received three doses of infliximab (5 mg/kg) as rescue therapy. This patient responded well to infliximab and was able to successfully taper off corticosteroids. In the inflammatory bowel disease population, infliximab is associated with an increased risk of severe infections, lymphoma, melanoma,
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
326 Melanoma Research
2015, Vol 25 No 4
and infusion reactions [12,16]. It should be used cautiously in immunocompromised melanoma patients treated with ipilimumab.
diarrhea. Nonetheless, the overall positive outcomes in this cohort likely reflect a focus on early recognition and treatment of ipilimumab-associated colitis.
Practice guidelines recommend that ipilimumab be discontinued in persistent grade 2 diarrhea despite treatment and in those with grade 3 or 4 diarrhea [13]. There are no guidelines on restarting ipilimumab in those who have developed ipilimumab-induced diarrhea. In our cohort, ipilimumab was only discontinued because of severe diarrhea (all grade 3) in six patients. Nineteen patients proceeded with ipilimumab therapy, despite having underlying diarrhea (10 with grade 3, four with grade 2, and five with grade 1). Half of these patients (50%, 7/14) with grade 2 and 3 diarrhea were on steroid (prednisone and/or budesonide) therapy while continuing their ipilimumab treatment. All seven of these patients had clinical improvement of their diarrhea on steroid therapy (median 9 days; range, 3–22 days) before receiving another dose of ipilimumab. All seven patients were able to complete their ipilimumab cycle (four doses). This suggests that early recognition of ipilimumab-induced colitis and prompt initiation of medical treatment often allows for continuation of ipilimumab therapy in those patients whose diarrhea is responsive to steroid therapy.
In conclusion, ipilimumab-induced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid-sparing agent, however, further studies examining its efficacy in this setting are needed. Infliximab can be used in refractory cases to avoid colectomy.
Three patients in our cohort who developed ipilimumabinduced diarrhea (two with grade 3 and one with grade 1) underwent a second cycle of ipilimumab. We successfully treated one patient prophylactically with high-dose budesonide (12 mg daily) before, during, and 1 month after the completion of the ipilimumab cycle (four doses). One patient developed severe diarrhea requiring hospitalization and intravenous steroids, and another patient is currently undergoing treatment with no diarrhea to date. Restarting ipilimumab in a patient who has developed ipilimumab-induced diarrhea with prior cycles should be made on a case-by-case basis. Using high-dose enteric release budesonide (12 mg daily) or budesonide MMX prophylactically can be considered when the benefits outweigh the risks. There are several studies suggesting that patients who experience immune-related adverse events with ipilimumab are more likely to have tumor regression; however, others have refuted this association [7,10,17]. We did not observe this in our study, as most patients with moderate-to-severe diarrhea had progression of their melanoma. We report one of the largest single center cohorts of ipilimumab-associated diarrhea. Although our experience adds important insights into the management of these patients, the number of cases remains too small to identify risk factors associated with the development of colitis. Given the retrospective nature of our study, we lacked endoscopy, infectious stool studies, and/or dedicated imaging for all of our patients who developed
Acknowledgements This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Conflicts of interest
Dr Edward Loftus, Jr. has consulted for, and has received research support from, Bristol-Myers Squibb. For the remaining authors there are no conflicts of interest.
References 1
Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo) 2013; 2013:857519. 2 O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 2007; 110:2614–2627. 3 Nancey S, Boschetti G, Cotte E, Ruel K, Almeras T, Chauvenet M, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab is associated with a profound long-lasting depletion of Foxp3 + regulatory T cells: a mechanistic explanation for ipilimumab-induced severe enterocolitis? Inflamm Bowel Dis 2012; 18:E1598–E1600. 4 Hodi F, O’Day S, McDermott D, Weber R, Sosman J, Haanen J, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723. 5 Ibrahim RBD, Berman DM, DePril V, Humphrey RW, Chen T, Messina M, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma [abstract]. J Clin Oncol 2011; 29:8583. 6 YERVOY (ipilimumab): serious and fatal immune-mediated adverse reactions. Ipilimumab US prescribing information: risk evaluation and mitigation strategy (REMS) B-MS, 2012. Available at: https://www.hcp. yervoy.com/pdf/rems-management-guide.pdf [Accessed October 2014]. 7 Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 2006; 24:2283–2289. 8 Kim KW, Ramaiya NH, Krajewski KM, Shinagare AB, Howard SA, Jagannathan JP, Ibrahim N. Ipilimumab-associated colitis: CT findings. Am J Roentgenol 2013; 200:W468–W474. 9 Berman D, Parker SM, Siegel J, Chasalow SD, Weber J, Galbraith S, 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. 10 Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 2007; 13 (Pt 1):6681–6688. 11 Harmankaya K, Erasim C, Koelblinger C, Ibrahim R, Hoos A, Pehamberger H, et al. Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy. Med Oncol 2011; 28:1140–1144. 12 Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn’s
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ipilimumab-induced colitis De Felice et al. 327
13
14
disease: more than 5 years of follow-up in the treat registry. Am J Gastroenterol 2012; 107:1409–1422. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30:2691–2697. Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, 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; 15:5591–5598.
15
Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of antiCTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm 2009; 24:321–325. 16 Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS, Kappelman MD. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology 2012; 143:390.e1–399.e1. 17 Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005; 23:6043–6053.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ipilimumab-induced colitis in patients with metastatic melanoma Kara M. De Felicea, Arjun Guptaa, Sagar Rakshita, Sahil Khannaa, Lisa A. Kottschadeb, Heidi D. Finnesb, Konstantinos A. Papadakisa, Edward V. Loftus Jra, Laura E. Raffalsa and Svetomir N. Markovicb Ipilimumab is used for the treatment of metastatic melanoma and is associated with serious immune-related colitis. We aimed to report the clinical features, treatment, and outcomes of patients with ipilimumab-induced colitis. In this retrospective observational study, we identified patients with unresectable melanoma treated with ipilimumab between March 2011 and September 2013. Diarrhea was assessed using the Common Terminology Criteria for Adverse Events, v3.0. Colitis was defined by diarrhea (grade ≥ 2) requiring steroids with or without endoscopic/histologic/radiologic evidence of colitis. A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades), and 23 patients (22%) developed colitis requiring systemic corticosteroid therapy. The median number of ipilimumab doses before onset of diarrhea was 2 (range, 1–4). Six of 23 patients responded to less than 1 mg/kg daily prednisone alone. Fifteen patients required high-dose oral and/or intravenous prednisone (1–2 mg/kg body weight). Six patients had diarrhea refractory to prednisone; five required rescue therapy with budesonide (9–12 mg daily) and one was treated with
Introduction One-third of patients treated with ipilimumab therapy for metastatic melanoma develop ipilimumab-induced colitis [1]. Ipilimumab is a fully human monoclonal antibody (IgG1) that targets cytotoxic T-lymphocyte antigen [2]. The immune dysregulation caused by the neutralization of regulatory cytotoxic T-lymphocyte antigen molecules on T cells and depletion of regulatory T cells has been associated with several immune-related adverse events, seen in ∼ 64% of patients treated with ipilimumab [3,4]. The most common adverse events involve the skin and luminal gastrointestinal tract; however, side effects including drug-induced hepatitis, adrenal insufficiency, hypothyroidism, hypophysitis, and neuropathy are also seen [1,5]. Most of these immune-related adverse events are mild-to-moderate, and are reversible with medical management. Less than 1% of immune-related adverse events have led to death [5]. Ipilimumab-induced colitis is a serious immune-related complication, and may lead to colonic perforation and death if left untreated [1]. Guidelines support treatment 0960-8931 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
infliximab (5 mg/kg, three doses). There was one case of severe diarrhea (grade 3) treated successfully with highdose budesonide (12 mg) monotherapy. Ipilimumabinduced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid-sparing agent, however further studies of its efficacy in this setting are needed. Infliximab should be used in refractory cases to avoid colectomy. Melanoma Res 25:321–327 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Melanoma Research 2015, 25:321–327 Keywords: budesonide, corticosteroids, immune-related adverse events, infliximab a Division of Gastroenterology and Hepatology and bDivision of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence to Svetomir N. Markovic, MD, PhD, Division of Medical Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA Tel: + 1 507 538 0118; fax: + 1 507 284 5045; e-mail: [email protected] Received 3 March 2015 Accepted 31 March 2015
with corticosteroids for moderate-to-severe colitis and infliximab or colectomy for refractory cases [6]. We report our experience describing the management and outcomes of 30 cases of ipilimumab-induced diarrhea.
Methods Study design
We conducted a retrospective observational study of patients with stage III/IV melanoma treated with ipilimumab between March 2011 and September 2013 at Mayo Clinic in Rochester, Minnesota, USA. The study was approved by the Ethics Committee and Institutional Review Board of the Mayo Clinic. Patients were identified using a pharmacy database. Patients who were 18 years of age and older, had a confirmed diagnosis of stage III/IV melanoma, treated with ipilimumab 3 mg/kg body weight every 3 weeks, and followed by the Division of Medical Oncology at Mayo Clinic, were included. Ipilimumab clinical trial patients were excluded. Patients who developed diarrhea within 3 months of ipilimumab therapy were identified. Diarrhea was DOI: 10.1097/CMR.0000000000000165
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
322 Melanoma Research
2015, Vol 25 No 4
assessed using the Common Terminology Criteria for Adverse Events (CTCAE), v3.0, (grade 1, < 4 stools per day; grade 2, 4–6 stools daily, abdominal pain, blood or mucus in the stool; grade 3, > 7 stools daily, severe abdominal pain, ileus, fever, peritoneal signs; and grade 4, life-threatening consequences). For the purpose of this study, colitis was defined by diarrhea (grade ≥ 2) requiring steroid therapy with or without endoscopic, histologic, radiologic evidence of colitis. Baseline characteristics including age, sex, smoking history, stage of melanoma, previous treatments, and ipilimumab therapy were documented. Infectious stool studies, endoscopies, and PET/computed tomography (CT) scans were recorded. Treatment regimen, dose, length of treatment, response, and treatment side effects were documented. There was no standardized treatment protocol used for the management of ipilimumab-induced colitis. Complete response was defined as the absence of diarrhea with bowel habits returning to the patient’s baseline, partial response as a decrease in bowel frequency, and no response as worsening or unchanged diarrhea. Statistical analysis
The baseline demographics and clinical characteristics of patients who developed ipilimumab-induced diarrhea were reported as percentages for categorical variables, mean with SD for continuous variables with normal distribution, and median with range for continuous variables with skewed distribution.
Results Patient characteristics
A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades) (Table 1). The median number of completed ipilimumab doses was 4 (range, 1–4). One patient received concomitant sargramostim. No patients received concomitant chemotherapy. Eight patients (27%) received concomitant radiation therapy, although the abdomen was not within the radiation field in any of the patients. Frequency of ipilimumab-induced diarrhea and colitis
Of the 30 patients who experienced diarrhea, 23 developed colitis (22% of the entire cohort). Eight patients within the ipilimumab cohort had previous exposure to ipilimumab; two of whom developed ipilimumabinduced colitis. The frequency of ipilimumab-induced diarrhea in ipilimumab-naive patients was 29% (28/95) and 22% (21/95) developed colitis. Clinical presentation
Five patients developed grade 1 diarrhea, six patients developed grade 2 diarrhea, and 19 patients developed grade 3 diarrhea (Table 2). The median number of ipilimumab doses completed before the onset of diarrhea was two doses
Table 1 Baseline demographics of patients who developed ipilimumab-induced diarrhea Demographics Median age at start of ipilimumab therapy (years) (range) Male Current smoker Current use of daily NSAIDS Personal history of autoimmune disease Metastatic melanoma Stage IV ECOG status = 0 Previous treatment with systemic chemotherapy Previous treatment with IL-2 Previous ipilimumab treatment Previous ipilimumab-induced diarrhea Treatment Median total number of ipilimumab doses completed [n (range)] Concomitant therapy Chemotherapy Radiation Surgery
N = 30 [n (%)] 63 (39–86) 17 1 6 4
(56) (3) (20) (13)
30 (100) 17/26 (65) (4 missing) 17 (57) 1 (3) 8 (27) 2 (25) 4 (1–4)
0 (0) 8 (27) 0 (0)
ECOG, Eastern Cooperative Oncology Group; IL-2, interleukin-2.
(range, 1–4). The majority (90%) of patients presented with watery stools. Only three patients (10%) had bloody stools; all with grade 3 diarrhea. Fifteen patients (50%) presented with abdominal pain and five patients (17%) were febrile at presentation. Diagnosis
A total of 23 patients (73.3% of the 30 patients with diarrhea) developed grade ≥ 2 diarrhea requiring steroid therapy resulting in a clinical diagnosis of colitis. Of these patients, four underwent CT scan to rule out bowel perforation. Only two of these four patients had radiographic evidence of colitis as demonstrated by colonic thickening on CT scan (Fig. 1b). Thirteen patients had diarrhea at the time of PET/CT performed for melanoma staging. Of these 13 patients, six had radiographic evidence of colitis on PET/CT (Fig. 1a). Stool tests to exclude infectious causes of diarrhea were performed at the onset of diarrhea in 15 patients (50%). None of the patients had an infectious etiology identified at initial presentation. Four patients, all with grade 3 diarrhea, underwent endoscopy, and colitis was evident in all. Endoscopic findings included diffuse erythematous, edematous mucosa with friability, exudate, and multiple superficial and deep ulcerations (Fig. 1c). Extensive colitis was seen in three patients and left-sided colitis in one patient. Histology showed active mild-to-moderate chronic colitis with ulcerations, crypt abscesses, and cryptitis (Fig. 1d). Three patients with endoscopic evidence of mild-tomoderate inflammation had a normal PET/CT, with no evidence of increased colonic uptake. Disease location based on endoscopy and/or radiographic images varied amongst patients [pancolitis (seven); left-sided colitis (two), right-sided colitis (one), and segmental colitis (one)].
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ipilimumab-induced colitis De Felice et al. 323
Table 2
Clinical characteristics and treatment of patients with ipilimumab-induced diarrhea Grade 1 (N = 5a)
Onset of diarrhea after median number of ipilimumab dose [n (range)] Colitis [n (%)] Imaging consistent with colitis [n (%)] Endoscopy consistent with colitis [n (%)] Treatment Low-dose prednisone (< 1 mg/kg) [n (%)] High-dose prednisone oral and/or intravenous (1–2 mg/kg) [n (%)] High-dose budesonide (9–12 mg) [n (%)] Infliximab (5 mg/kg) [n (%)] Median duration of total steroid treatment [days (range)] Median duration of prednisone treatment [days (range)] Median duration of budesonide treatment [days (range)] Median days on total steroids to complete response [days (range)] Median days on budesonide to complete response [days (range)] Complete response to treatment [n (%)] Ipilimumab-induced complications [n (%)] Infectious colitis Colectomy or perforations Hospitalizations for diarrhea Steroid-induced complications [n (%)] Adrenal insufficiency Myopathy Concomitant immune-related adverse events [n (%)] Hepatitis Rash Adrenal insufficiency Hypothyroidism Tumor response to ipilimumab treatment [n (%)] Stable disease Partial response Complete response Progressive disease
1 0 0/1 0/0
Grade 2 (N = 6a)
(1–2) (0) (0) (0)
1 4 1/2 0/0
(0) (0) (0) (0) 0 0 0 0 0 5 (100)
4 0 0 0 11 11
0 0 0 0
(1–3) (67) (50) (0)
(67) (0) (0) (0) (2–79) (2–79) 0 11 (2–74) 0 6 (100)
Grade 3 (N = 19a) 2 19 7/15 4/4
(1–4) (100) (47) (100)
2 15 7 1 80 75 110 58 63 19
(11) (79) (37) (5) (32–175) (32–163) (42–157) (12–120) (13–157) (100)
Total (N = 30a) 2 23 8/18 4/4 6 15 7 1 75 68 110 50 63 30
(1–4) (77) (44) (100) (20) (50) (23) (3) (2–175) (2–163) (42–157) (2–120) (13–157) (100)
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 1 (17)
2 (11) 0 (0) 14 (74)
2 (7) 0 (0) 15 (50)
0/0 (0) 0/0 (0)
1/4 (25) 0/4 (0)
2 (11) 1 (5)
3/23 (13) 1/23 (4)
0 2 0 1
(0) (40) (0) (20)
1 1 0 1
(17) (17) (0) (17)
1 2 2 1
(5) (11) (11) (5)
6 5 2 3
(20) (17) (7) (10)
0 1 1 3
(0) (20) (20) (60)
0 1 0 5
(0) (17) (0) (83)
3 3 0 13
(16) (16) (0) (68)
3 4 1 21
(10) (13) (3) (70)
Grade 1; < 4 stools daily. Grade 2; 4–6 stools daily, abdominal pain, blood/mucous stools. Grade 3; > 7 stools daily, severe abdominal pain, ileus, fever, and peritoneal signs. Grade 4; diarrhea with life-threatening consequences. a Denominator is N unless otherwise stated.
Management and treatment response
All patients (n = 5) with grade 1 diarrhea and two of six patients with grade 2 diarrhea were treated symptomatically with loperamide (2–16 mg daily). The remaining four patients with grade 2 diarrhea improved with oral prednisone monotherapy (< 1 mg/kg, 20–50 mg daily, 2–79 days duration). Two of 19 patients with grade 3 diarrhea improved with oral prednisone monotherapy (< 1 mg/kg, 30–60 mg daily, 32–75 days duration). Fifteen patients with grade 3 diarrhea required high-dose oral prednisone (1–2 mg/kg, 60–200 mg daily, 40–165 days duration). Six of these 15 patients also received intravenous corticosteroids (50–1000 mg methylprednisolone daily, median duration 3 days, range 1–6 days). Of the 23 patients who received prednisone, six (26%) had prednisone-refractory diarrhea. Five patients were given a course of oral delayed-release budesonide (9–12 mg daily) despite failing prednisone, and one patient received infliximab (5 mg/kg, three doses). All patients who received budesonide had a complete response and were able to tolerate a prednisone taper by 5–10 mg weekly (median 57 days, range 26–110 days). The one patient treated with infliximab rescue therapy received three doses (5 mg/kg at 0, 2, and 6 weeks) and
was started on budesonide therapy after the first dose of infliximab. After the start of budesonide therapy, the patient was able to titrate off prednisone 60 mg daily in 26 days. The patient had complete resolution of diarrhea 18 days after the first dose of infliximab. There was a single case of severe diarrhea (grade 3) treated successfully with high-dose budesonide (12 mg) monotherapy tapered over 5 months. The median time of onset of symptoms to treatment was 3 days (range, 0–53 days). Median duration of total steroid treatment was 75 days (range, 2–175 days); including prednisone, 68 days (range, 2–163 days) and budesonide, 110 days (range, 42–157 days). The median time of total steroid therapy to complete response was 50 days (range, 2–120 days). The median time of budesonide therapy to complete response was 63 days (range, 13–157 days). Patients with grade 3 diarrhea required longer duration of total steroid, prednisone, and budesonide therapy and had a longer time to complete response (Table 2). Ipilimumab was continued in many of our patients (19/30, 63%) despite the presence of diarrhea. Ipilimumab was discontinued in six patients because of their underlying diarrhea (all with grade 3 diarrhea) and in three patients due to progression of melanoma. The
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
324 Melanoma Research
2015, Vol 25 No 4
Fig. 1
Ipilimumab-induced colitis. (a) Increased fludeoxyglucose (18F) uptake in large intestine suggestive of ipilimumab-induced colitis on PET/CT. (b) Diffuse ipilimumab-colitis as marked by thickening of the entire colon on CT enterography. (c) Ipilimumab-induced colitis on colonoscopy, with edema, loss of vascular pattern, increased granularity, and ulcerations. (d) Moderate active chronic colitis without granulomas, shortened crypts, cryptitis, and crypt abscesses on colon biopsy. CT, computed tomography.
other two patients developed diarrhea after completion of their ipilimumab cycle (four doses) and did not proceed with a second cycle. All patients (any diarrhea grade) had complete resolution of diarrhea symptoms with medical therapy (antidiarrheals, corticosteroid or infliximab) and/or discontinuing ipilimumab.
There were a total of 15 hospitalizations and four emergency department visits for diarrhea. No patient required intensive care unit management. All hospitalized patients received intravenous fluid and electrolyte replacement and one patient required packed red blood cell transfusions due to anemia. Two patients received empiric systemic antibiotics.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ipilimumab-induced colitis De Felice et al. 325
No patients required total parenteral nutrition. There were no colonic perforations nor need for colectomy. The majority of patients had progression of their metastatic melanoma at the end of ipilimumab therapy irrespective of the grade of ipilimumab-induced diarrhea. Adverse events
Two patients developed superimposed infectious colitis (Clostridium difficile and Campylobacter jejuni) and were treated successfully with antibiotics. There were no deaths related to ipilimumab-induced colitis. Steroidinduced side effects and concomitant immune-related adverse events are summarized in Table 2. Restarting ipilimumab
Only three patients with ipilimumab-induced diarrhea (two with grade 3 and one with grade 1) were rechallenged with a second cycle of ipilimumab. One patient was started prophylactically on 12 mg of budesonide before and 1 month after ipilimumab therapy and never developed ipilimumab-induced diarrhea. One patient developed severe ipilimumab-induced colitis requiring hospitalization and intravenous steroids. Another patient is currently undergoing another ipilimumab cycle with no diarrhea to date after one dose.
Discussion Ipilimumab-induced colitis is a serious immune-related adverse event that warrants early recognition and aggressive medical therapy. It can be successfully managed with systemic corticosteroids, high-dose budesonide, and infliximab in refractory cases. Colectomy should be used as a last resort. Similar to other reports in the literature, we noted a 29% overall frequency of diarrhea despite previous treatment with ipilimumab. Patients in our cohort were more likely to have colitis (22 vs. 8%).[4,5] The higher incidence of colitis in our study is most likely explained by our definition of colitis, which differs from other studies. We used a clinical diagnosis of colitis, compared with the CTCAE v3.0, which requires endoscopic or radiologic evidence of colitis. We found an inconsistent correlation between endoscopic and radiologic evidence of colitis in symptomatic patients. The literature also reports normal endoscopic evaluations with histologic findings consistent with ipilimumab-induced colitis [7]. Therefore, we believe that in the proper clinical setting, one can use the severity of clinical symptoms with endoscopic and histologic evidence of colitis to help guide treatment. Only half of our patients had stool studies done to rule out infectious colitis. Two patients developed superimposed infectious colitis. This finding highlights the need for a standardized practice guideline for the management of this patient cohort, which should always include stool studies to exclude infectious causes of
colitis. The endoscopic and histologic findings are similar to inflammatory bowel disease; however, there were no key distinguishing features. Diffuse inflammation was seen in a subset of our cohort, and a similar diffuse colitis has been described in the literature [8]. Nonspecific histopathologic findings showing acute and chronic inflammation have been reported, and we observed similar histopathologic findings [9]. In our cohort, only four patients underwent endoscopic evaluation (all four in consultation with gastroenterology). Endoscopic evaluation should be reserved for those patients with persistent grade 1 and moderate-to-severe diarrhea (grade ≥ 2). Biopsies should be performed to exclude cytomegalovirus colitis. Half of our patients required high doses of prednisone (1–2 mg/kg oral and/or intravenous) for the treatment of ipilimumab-induced colitis. There is a theoretical concern that the use of corticosteroids to manage immunerelated adverse events may dampen the immune-driven efficacy of ipilimumab. Although this has not been demonstrated clinically, published studies are small and further investigation is warranted [10,11]. The use of long-term corticosteroids has been associated with many side effects, and has been shown to increase mortality and the risk of severe infections in patients with Crohn’s disease [12]. In our study, the use of prednisone was associated with steroid-induced side effects in 17% of patients, including three patients who required long-term prednisone therapy for secondary adrenal insufficiency. Six patients had diarrhea refractory to prednisone of whom five required rescue therapy with high-dose oral budesonide (9–12 mg daily). Budesonide therapy was associated with longer overall treatment duration, but was safer with fewer corticosteroid-induced side effects compared with long-term high-dose prednisone. Theoretically, higher doses of budesonide, 12 mg daily, may be more effective in the treatment of colitis as more drug is delivered to the distal colon. Budesonide, 9 mg daily, has been suggested as a treatment for mild-tomoderate (grade 1–2) ipilimumab-associated colitis [6, 13]. In contrast, in a double-blind, randomized phase II controlled trial of ipilimumab with or without prophylactic budesonide (9 mg daily), those treated with prophylactic budesonide did not show a decreased rate of grade ≥ 2 diarrhea compared with placebo. Therefore, budesonide has not been recommended to be used as prophylaxis [14]. However, it has not been studied for treatment of ipilimumab-induced colitis. Infliximab has been used for steroid-refractory severe (grade 3–4) diarrhea in patients with ipilimumab-induced colitis [13,15]. In our study, only one patient received three doses of infliximab (5 mg/kg) as rescue therapy. This patient responded well to infliximab and was able to successfully taper off corticosteroids. In the inflammatory bowel disease population, infliximab is associated with an increased risk of severe infections, lymphoma, melanoma,
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
326 Melanoma Research
2015, Vol 25 No 4
and infusion reactions [12,16]. It should be used cautiously in immunocompromised melanoma patients treated with ipilimumab.
diarrhea. Nonetheless, the overall positive outcomes in this cohort likely reflect a focus on early recognition and treatment of ipilimumab-associated colitis.
Practice guidelines recommend that ipilimumab be discontinued in persistent grade 2 diarrhea despite treatment and in those with grade 3 or 4 diarrhea [13]. There are no guidelines on restarting ipilimumab in those who have developed ipilimumab-induced diarrhea. In our cohort, ipilimumab was only discontinued because of severe diarrhea (all grade 3) in six patients. Nineteen patients proceeded with ipilimumab therapy, despite having underlying diarrhea (10 with grade 3, four with grade 2, and five with grade 1). Half of these patients (50%, 7/14) with grade 2 and 3 diarrhea were on steroid (prednisone and/or budesonide) therapy while continuing their ipilimumab treatment. All seven of these patients had clinical improvement of their diarrhea on steroid therapy (median 9 days; range, 3–22 days) before receiving another dose of ipilimumab. All seven patients were able to complete their ipilimumab cycle (four doses). This suggests that early recognition of ipilimumab-induced colitis and prompt initiation of medical treatment often allows for continuation of ipilimumab therapy in those patients whose diarrhea is responsive to steroid therapy.
In conclusion, ipilimumab-induced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid-sparing agent, however, further studies examining its efficacy in this setting are needed. Infliximab can be used in refractory cases to avoid colectomy.
Three patients in our cohort who developed ipilimumabinduced diarrhea (two with grade 3 and one with grade 1) underwent a second cycle of ipilimumab. We successfully treated one patient prophylactically with high-dose budesonide (12 mg daily) before, during, and 1 month after the completion of the ipilimumab cycle (four doses). One patient developed severe diarrhea requiring hospitalization and intravenous steroids, and another patient is currently undergoing treatment with no diarrhea to date. Restarting ipilimumab in a patient who has developed ipilimumab-induced diarrhea with prior cycles should be made on a case-by-case basis. Using high-dose enteric release budesonide (12 mg daily) or budesonide MMX prophylactically can be considered when the benefits outweigh the risks. There are several studies suggesting that patients who experience immune-related adverse events with ipilimumab are more likely to have tumor regression; however, others have refuted this association [7,10,17]. We did not observe this in our study, as most patients with moderate-to-severe diarrhea had progression of their melanoma. We report one of the largest single center cohorts of ipilimumab-associated diarrhea. Although our experience adds important insights into the management of these patients, the number of cases remains too small to identify risk factors associated with the development of colitis. Given the retrospective nature of our study, we lacked endoscopy, infectious stool studies, and/or dedicated imaging for all of our patients who developed
Acknowledgements This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Conflicts of interest
Dr Edward Loftus, Jr. has consulted for, and has received research support from, Bristol-Myers Squibb. For the remaining authors there are no conflicts of interest.
References 1
Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo) 2013; 2013:857519. 2 O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 2007; 110:2614–2627. 3 Nancey S, Boschetti G, Cotte E, Ruel K, Almeras T, Chauvenet M, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab is associated with a profound long-lasting depletion of Foxp3 + regulatory T cells: a mechanistic explanation for ipilimumab-induced severe enterocolitis? Inflamm Bowel Dis 2012; 18:E1598–E1600. 4 Hodi F, O’Day S, McDermott D, Weber R, Sosman J, Haanen J, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723. 5 Ibrahim RBD, Berman DM, DePril V, Humphrey RW, Chen T, Messina M, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma [abstract]. J Clin Oncol 2011; 29:8583. 6 YERVOY (ipilimumab): serious and fatal immune-mediated adverse reactions. Ipilimumab US prescribing information: risk evaluation and mitigation strategy (REMS) B-MS, 2012. Available at: https://www.hcp. yervoy.com/pdf/rems-management-guide.pdf [Accessed October 2014]. 7 Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 2006; 24:2283–2289. 8 Kim KW, Ramaiya NH, Krajewski KM, Shinagare AB, Howard SA, Jagannathan JP, Ibrahim N. Ipilimumab-associated colitis: CT findings. Am J Roentgenol 2013; 200:W468–W474. 9 Berman D, Parker SM, Siegel J, Chasalow SD, Weber J, Galbraith S, 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. 10 Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 2007; 13 (Pt 1):6681–6688. 11 Harmankaya K, Erasim C, Koelblinger C, Ibrahim R, Hoos A, Pehamberger H, et al. Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy. Med Oncol 2011; 28:1140–1144. 12 Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn’s
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ipilimumab-induced colitis De Felice et al. 327
13
14
disease: more than 5 years of follow-up in the treat registry. Am J Gastroenterol 2012; 107:1409–1422. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30:2691–2697. Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, 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; 15:5591–5598.
15
Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of antiCTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm 2009; 24:321–325. 16 Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS, Kappelman MD. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology 2012; 143:390.e1–399.e1. 17 Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005; 23:6043–6053.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
