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Ipilimumab- and Nivolumab-Induced Colitis Causing Severe Hypokalemia and QTc Prolongation

Ipilimumab- and Nivolumab-Induced Colitis Causing Severe Hypokalemia and QTc Prolongation Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 7896749, 2 pages https://doi.org/10.1155/2019/7896749 Case Report Ipilimumab- and Nivolumab-Induced Colitis Causing Severe Hypokalemia and QTc Prolongation 1 2 2 2 David Anson , Joseph Norton , Benjamin Chaucer , and Saurabh Bansal University of Illinois College of Medicine Peoria, Peoria, IL, USA Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL, USA Correspondence should be addressed to David Anson; danson2@uic.edu Received 14 September 2019; Revised 27 November 2019; Accepted 7 December 2019; Published 27 December 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 David Anson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immune-mediated colitis is an uncommon but well-documented adverse event in patients receiving nivolumab or ipilimumab therapy. In this report, we present a 69-year-old man who developed severe hypokalemia and colitis with significant corrected Q-T segment (QTc) prolongation as a result of combination nivolumab-ipilimumab immunotherapy for clear cell renal cell carcinoma. 1. Introduction of 9 mmol/L. Abdominal radiography (KUB) showed gaseous distention of the small and large bowel and likely ileus. CT We present the unique findings of severe hypokalemia imaging was not conducted. Due to high risk of perforation and immune-mediated colitis from ipilimumab and nivo- in the acute setting, colonoscopy was not performed. Gentle lumab combination immunotherapy for clear cell renal cell fluid resuscitation, aggressive potassium repletion, and serial carcinoma. The broad differential for severe diarrhea and electrolyte monitoring were initiated. Stool studies for ova, electrolyte imbalance in a patient with malignancy and parasites, Clostridium difficile, Salmonella, and bacterial immunocompromised status receiving novel chemothera- enterotoxins were negative. Stool lactoferrin was positive. peutic agents presents a significant diagnostic challenge. Adrenal insufficiency was suspected, but ruled out with nor- mal morning cortisol and adrenocorticotropin stimulation 2. Case Description testing. Thyroid hormone levels were normal. A diagnosis of immunotherapy-induced colitis was made. Treatment A 69-year-old man with a past medical history of metastatic with intravenous methyl-prednisolone 60 mg daily for four renal cell carcinoma, diabetes mellitus type 2, and chronic days was initiated, and the patient’s condition significantly kidney disease presented with a 2-month duration of fre- improved. Diarrhea slowed down, electrolytes normalized, quent watery stools not relieved by metronidazole, atro- and EKG showed QTc improvement at 538 ms. After discus- pine-diphenoxylate, or loperamide. He reported 10-12 sion with oncology, ipilimumab and nivolumab therapy was loose, watery, brown, mucousy stools daily without gross discontinued. He was discharged home with a four-week oral blood or associated abdominal pain. The frequency and sever- steroid taper regimen. The taper schedule was prednisone ity of diarrhea had progressively worsened over the last 50 mg for two weeks, followed by 30 mg for five days, then month. Combination immunomodulatory therapy of ipilimu- 20 mg for five days, and finally 10 mg for four days. mab and nivolumab was started 3 months prior to arrival. He received his last therapy cycle 1 week prior to hospitalization. On admission, he presented with hypokalemia of 2.2 mmol/L, 3. Discussion creatinine of 2.59 mg/dL, and orthostatic hypotension. Elec- trocardiogram (EKG) demonstrated QTc prolongation at This case illustrates the potential for severe electrolyte 725 ms, normal anion gap metabolic acidosis with bicarbonate imbalance from immune-mediated colitis with the use of 2 Case Reports in Oncological Medicine to the traditional guidance of lower dose treatment, which Table 1: Common Terminology Criteria for Adverse Events grading scale in immune checkpoint inhibitor-induced colitis and may prolong hospitalization [7]. Treatment strategy of com- diarrhea. bination ipilimumab-nivolumab colitis consists of cessation of immunomodulatory therapy, initiation of steroid therapy, Colitis Diarrhea and supportive treatment. In steroid-refractory cases, inflixi- Grade 1 Asymptomatic Increase of <4 stools/day mab or vedolizumab therapy may be utilized as a second-line Abdominal pain, regimen. In addition, fecal microbiota transplantation may Grade 2 Increase of 4-6 stools/day mucus, blood in stool be considered in patients in which steroid and anti-TNF Severe pain, fever, therapies have proven unsuccessful (1). Careful surveillance Grade 3 Increase of ≥7 stools/day peritoneal signs of serum potassium during steroid therapy is recommended, as corticosteroids may cause hypokalemia. This is especially Life-threatening Life-threatening consequences pertinent during ongoing gastrointestinal losses when there consequences such Grade 4 (perforation, ischemia, is minimal improvement after several days of steroid as hemodynamic necrosis, bleeding, administration. collapse toxic megacolon) Grade 5 Death Death 4. Conclusion immunotherapeutic agents. Immune-mediated colitis is a The broad range of possible presentations in immunotherapy- well-documented adverse effect of immune checkpoint induced dysfunction may prove a particularly challenging inhibitors (ICIs), with an incidence ranging from 1 to 25% entity to identify and treat appropriately. Unfortunately, depending on the ICI and whether the therapy is single agent immunotherapeutic side effect profiles are not well known or combination [1]. In addition, combined anti-CTLA4 and within the medical community. As the use of immunotherapy anti-PD-1 therapy significantly increases the frequency and becomes more prevalent, prompt diagnosis and cessation of severity of immune-mediated colitis (1). The National Insti- the offending agent, initiation of treatment with steroids, and tutes of Health and National Cancer Institute “Common Ter- supportive treatment in immunotherapy-induced colitis are minology Criteria for Adverse Events” (CTCAE) grading vital to preventing unfavorable outcomes. schema may be helpful for characterizing the severity of immune checkpoint inhibitor-induced colitis [2]. Based on Conflicts of Interest the CTCAE grading scale, our patient would be categorized as grade 2 colitis, due to mucus in the stool, and grade 4 diar- We have no conflicts of interest to report. rhea, due to severe electrolyte derangement with profound widening of the Q-R-S complex evidenced by QTc prolonga- References tion (see Table 1). Previous case reports have described severe colitis second- [1] A. Som, R. Mandaliya, D. Alsaadi et al., “Immune checkpoint ary to combined ipilimumab and nivolumab therapy refrac- inhibitor-induced colitis: a comprehensive review,” World Jour- tory to high-dose steroid therapy [3]. While our patient nal of Clinical Cases, vol. 7, no. 4, pp. 405–418, 2019. demonstrated a rapid improvement after initiation of steroids, [2] National Institute of Health; National Cancer Institute, “Com- up to 40% of cases may require initiation of infliximab as a mon Terminology Criteria for Adverse Events v5.0.,” 2017, second-line therapy (4). Like the majority of cases reported https://ctep.cancer.gov/protocolDevelopment/electronic_ applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. in the literature, our patient developed severe diarrhea and worsening colitis shortly after receiving his third cycle of com- [3] A. Nassri, V. Muenyi, B. De Souza Ribeiro, J. Scolapio, and M. d. Malespin, “Ipilimumab and nivolumab induced steroid- bination therapy. Risk factors for the development of ICI- refractory colitis treated with infliximab: a case report,” World induced colitis include history of autoimmune diseases, non- Journal of Gastrointestinal Pharmacology and Therapeutics, steroidal anti-inflammatory drug use, and baseline gut micro- vol. 10, no. 1, pp. 29–34, 2019. biome composition (1). Other documented, serious adverse [4] R. Bajwa, A. Cheema, T. Khan et al., “Adverse effects of effects include hepatitis, adrenal insufficiency, hypothyroid- immune checkpoint inhibitors (programmed death-1 inhibi- ism, pancreatic dysfunction, and myocarditis [4]. tors and cytotoxic T-lymphocyte-associated protein-4 inhibi- While the occurrence and treatment of these conditions tors): results of a retrospective study,” Journal of Clinical have been documented, the exact mechanism by which these Medicine Research, vol. 11, no. 4, pp. 225–236, 2019. events occur is not well understood. In nivolumab, current [5] S. Yanai, S. Nakamura, and T. Matsumoto, “Nivolumab- hypotheses suggest a role of T-cell activation by the antibody induced colitis treated by infliximab,” Clinical Gastroenterology which results in an enhanced immune response and that this and Hepatology, vol. 15, no. 4, pp. 80-81, 2017. effect may be compounded in the presence of ipilimumab [6] R. Yamauchi, T. Araki, K. Mitsuyama et al., “The characteristics [5]. Interestingly, nivolumab-induced colitis exhibits endo- of nivolumab-induced colitis: an evaluation of three cases and a scopic features similar to that of ulcerative colitis (UC) and literature review,” BMC Gastroenterology, vol. 18, no. 1, p. 135, may have a therapeutic response to agents such as mesalazine typically used in UC and other inflammatory bowel disease [7] H. Walker, P. Brennan, M. Groome, S. Walsh, and F. Carey, [6]. Recently, clinicians have also documented faster resolu- “Nivolumab and immune-mediated colitis,” Clinical Case tion of symptoms with high-dose steroid therapy as opposed Reports, vol. 7, no. 4, pp. 644–647, 2019. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Hindawi Publishing Corporation Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 http://www www.hindawi.com .hindawi.com V Volume 2018 olume 2013 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 International Journal of Journal of Immunology Research Endocrinology Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Submit your manuscripts at www.hindawi.com BioMed PPAR Research Research International Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2013 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Neurology Research and Treatment Cellular Longevity Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Ipilimumab- and Nivolumab-Induced Colitis Causing Severe Hypokalemia and QTc Prolongation

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Hindawi Publishing Corporation
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Copyright © 2019 David Anson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2090-6706
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10.1155/2019/7896749
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 7896749, 2 pages https://doi.org/10.1155/2019/7896749 Case Report Ipilimumab- and Nivolumab-Induced Colitis Causing Severe Hypokalemia and QTc Prolongation 1 2 2 2 David Anson , Joseph Norton , Benjamin Chaucer , and Saurabh Bansal University of Illinois College of Medicine Peoria, Peoria, IL, USA Department of Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, IL, USA Correspondence should be addressed to David Anson; danson2@uic.edu Received 14 September 2019; Revised 27 November 2019; Accepted 7 December 2019; Published 27 December 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 David Anson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immune-mediated colitis is an uncommon but well-documented adverse event in patients receiving nivolumab or ipilimumab therapy. In this report, we present a 69-year-old man who developed severe hypokalemia and colitis with significant corrected Q-T segment (QTc) prolongation as a result of combination nivolumab-ipilimumab immunotherapy for clear cell renal cell carcinoma. 1. Introduction of 9 mmol/L. Abdominal radiography (KUB) showed gaseous distention of the small and large bowel and likely ileus. CT We present the unique findings of severe hypokalemia imaging was not conducted. Due to high risk of perforation and immune-mediated colitis from ipilimumab and nivo- in the acute setting, colonoscopy was not performed. Gentle lumab combination immunotherapy for clear cell renal cell fluid resuscitation, aggressive potassium repletion, and serial carcinoma. The broad differential for severe diarrhea and electrolyte monitoring were initiated. Stool studies for ova, electrolyte imbalance in a patient with malignancy and parasites, Clostridium difficile, Salmonella, and bacterial immunocompromised status receiving novel chemothera- enterotoxins were negative. Stool lactoferrin was positive. peutic agents presents a significant diagnostic challenge. Adrenal insufficiency was suspected, but ruled out with nor- mal morning cortisol and adrenocorticotropin stimulation 2. Case Description testing. Thyroid hormone levels were normal. A diagnosis of immunotherapy-induced colitis was made. Treatment A 69-year-old man with a past medical history of metastatic with intravenous methyl-prednisolone 60 mg daily for four renal cell carcinoma, diabetes mellitus type 2, and chronic days was initiated, and the patient’s condition significantly kidney disease presented with a 2-month duration of fre- improved. Diarrhea slowed down, electrolytes normalized, quent watery stools not relieved by metronidazole, atro- and EKG showed QTc improvement at 538 ms. After discus- pine-diphenoxylate, or loperamide. He reported 10-12 sion with oncology, ipilimumab and nivolumab therapy was loose, watery, brown, mucousy stools daily without gross discontinued. He was discharged home with a four-week oral blood or associated abdominal pain. The frequency and sever- steroid taper regimen. The taper schedule was prednisone ity of diarrhea had progressively worsened over the last 50 mg for two weeks, followed by 30 mg for five days, then month. Combination immunomodulatory therapy of ipilimu- 20 mg for five days, and finally 10 mg for four days. mab and nivolumab was started 3 months prior to arrival. He received his last therapy cycle 1 week prior to hospitalization. On admission, he presented with hypokalemia of 2.2 mmol/L, 3. Discussion creatinine of 2.59 mg/dL, and orthostatic hypotension. Elec- trocardiogram (EKG) demonstrated QTc prolongation at This case illustrates the potential for severe electrolyte 725 ms, normal anion gap metabolic acidosis with bicarbonate imbalance from immune-mediated colitis with the use of 2 Case Reports in Oncological Medicine to the traditional guidance of lower dose treatment, which Table 1: Common Terminology Criteria for Adverse Events grading scale in immune checkpoint inhibitor-induced colitis and may prolong hospitalization [7]. Treatment strategy of com- diarrhea. bination ipilimumab-nivolumab colitis consists of cessation of immunomodulatory therapy, initiation of steroid therapy, Colitis Diarrhea and supportive treatment. In steroid-refractory cases, inflixi- Grade 1 Asymptomatic Increase of <4 stools/day mab or vedolizumab therapy may be utilized as a second-line Abdominal pain, regimen. In addition, fecal microbiota transplantation may Grade 2 Increase of 4-6 stools/day mucus, blood in stool be considered in patients in which steroid and anti-TNF Severe pain, fever, therapies have proven unsuccessful (1). Careful surveillance Grade 3 Increase of ≥7 stools/day peritoneal signs of serum potassium during steroid therapy is recommended, as corticosteroids may cause hypokalemia. This is especially Life-threatening Life-threatening consequences pertinent during ongoing gastrointestinal losses when there consequences such Grade 4 (perforation, ischemia, is minimal improvement after several days of steroid as hemodynamic necrosis, bleeding, administration. collapse toxic megacolon) Grade 5 Death Death 4. Conclusion immunotherapeutic agents. Immune-mediated colitis is a The broad range of possible presentations in immunotherapy- well-documented adverse effect of immune checkpoint induced dysfunction may prove a particularly challenging inhibitors (ICIs), with an incidence ranging from 1 to 25% entity to identify and treat appropriately. Unfortunately, depending on the ICI and whether the therapy is single agent immunotherapeutic side effect profiles are not well known or combination [1]. In addition, combined anti-CTLA4 and within the medical community. As the use of immunotherapy anti-PD-1 therapy significantly increases the frequency and becomes more prevalent, prompt diagnosis and cessation of severity of immune-mediated colitis (1). The National Insti- the offending agent, initiation of treatment with steroids, and tutes of Health and National Cancer Institute “Common Ter- supportive treatment in immunotherapy-induced colitis are minology Criteria for Adverse Events” (CTCAE) grading vital to preventing unfavorable outcomes. schema may be helpful for characterizing the severity of immune checkpoint inhibitor-induced colitis [2]. Based on Conflicts of Interest the CTCAE grading scale, our patient would be categorized as grade 2 colitis, due to mucus in the stool, and grade 4 diar- We have no conflicts of interest to report. rhea, due to severe electrolyte derangement with profound widening of the Q-R-S complex evidenced by QTc prolonga- References tion (see Table 1). Previous case reports have described severe colitis second- [1] A. Som, R. Mandaliya, D. Alsaadi et al., “Immune checkpoint ary to combined ipilimumab and nivolumab therapy refrac- inhibitor-induced colitis: a comprehensive review,” World Jour- tory to high-dose steroid therapy [3]. While our patient nal of Clinical Cases, vol. 7, no. 4, pp. 405–418, 2019. demonstrated a rapid improvement after initiation of steroids, [2] National Institute of Health; National Cancer Institute, “Com- up to 40% of cases may require initiation of infliximab as a mon Terminology Criteria for Adverse Events v5.0.,” 2017, second-line therapy (4). Like the majority of cases reported https://ctep.cancer.gov/protocolDevelopment/electronic_ applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. in the literature, our patient developed severe diarrhea and worsening colitis shortly after receiving his third cycle of com- [3] A. Nassri, V. Muenyi, B. De Souza Ribeiro, J. Scolapio, and M. d. Malespin, “Ipilimumab and nivolumab induced steroid- bination therapy. Risk factors for the development of ICI- refractory colitis treated with infliximab: a case report,” World induced colitis include history of autoimmune diseases, non- Journal of Gastrointestinal Pharmacology and Therapeutics, steroidal anti-inflammatory drug use, and baseline gut micro- vol. 10, no. 1, pp. 29–34, 2019. biome composition (1). Other documented, serious adverse [4] R. Bajwa, A. Cheema, T. Khan et al., “Adverse effects of effects include hepatitis, adrenal insufficiency, hypothyroid- immune checkpoint inhibitors (programmed death-1 inhibi- ism, pancreatic dysfunction, and myocarditis [4]. tors and cytotoxic T-lymphocyte-associated protein-4 inhibi- While the occurrence and treatment of these conditions tors): results of a retrospective study,” Journal of Clinical have been documented, the exact mechanism by which these Medicine Research, vol. 11, no. 4, pp. 225–236, 2019. events occur is not well understood. In nivolumab, current [5] S. Yanai, S. Nakamura, and T. Matsumoto, “Nivolumab- hypotheses suggest a role of T-cell activation by the antibody induced colitis treated by infliximab,” Clinical Gastroenterology which results in an enhanced immune response and that this and Hepatology, vol. 15, no. 4, pp. 80-81, 2017. effect may be compounded in the presence of ipilimumab [6] R. Yamauchi, T. Araki, K. Mitsuyama et al., “The characteristics [5]. Interestingly, nivolumab-induced colitis exhibits endo- of nivolumab-induced colitis: an evaluation of three cases and a scopic features similar to that of ulcerative colitis (UC) and literature review,” BMC Gastroenterology, vol. 18, no. 1, p. 135, may have a therapeutic response to agents such as mesalazine typically used in UC and other inflammatory bowel disease [7] H. Walker, P. Brennan, M. Groome, S. Walsh, and F. Carey, [6]. Recently, clinicians have also documented faster resolu- “Nivolumab and immune-mediated colitis,” Clinical Case tion of symptoms with high-dose steroid therapy as opposed Reports, vol. 7, no. 4, pp. 644–647, 2019. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Hindawi Publishing Corporation Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 http://www www.hindawi.com .hindawi.com V Volume 2018 olume 2013 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 International Journal of Journal of Immunology Research Endocrinology Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Submit your manuscripts at www.hindawi.com BioMed PPAR Research Research International Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2013 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Neurology Research and Treatment Cellular Longevity Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018

Journal

Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Dec 27, 2019

References