Evaluation and Management of Suspected Immune-Mediated Page 1 of 10 Colitis/Diarrhea Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. GENERAL EVALUATION PRESENTATION ASSESSMENT TREATMENT Hold immunotherapy and order the following: ● Initiate appropriate ● Gastrointestinal (GI) consult therapy 6 ● GI Multiplex PCR panel and fecal CMV PCR ● Consider Infectious ● Consider infectious workup for non-GI organs if there is Diseases consult fever or symptoms suggesting individual organ involvement Yes ● CT abdomen/pelvis with oral and IV contrast Moderate/ Alternate ● Laboratory evaluation: CBC, complete metabolic cause(s) of severe colitis panel (CMP), amylase, lipase, and ANA colitis (Grade 2 and ● 5 Inflammatory blood markers: ESR and CRP above) found? No Patient presents Yes ● Inflammatory stool markers: lactoferrin and calprotectin with new onset of ● Fecal pancreatic elastase to rule out exocrine pancreatic diarrhea1 one week Is diarrhea insufficiency For further assessment/ after immuno- associated with ● Total IgA and tissue transglutaminase (tTG) IgA to rule management, see Page 2 therapy initiation colitis out celiac disease 4 7 and up to 6 months2 symptoms ? ● Screening tests , if not drawn within the past 6-12 months after last dose of 3 No immunotherapy Diarrhea alone For assessment and treatment of diarrhea, see Page 4 For recurrent colitis/diarrhea assessment and treatment, see Page 5 1 Diarrhea is defined as the presence of 3 or more unformed stools a day CMV = cytomegalovirus 2 On rare occasions, GI toxicities may develop beyond the typical 6 month window ANA = antinuclear antibodies 3 PD-1 inhibitors (pembrolizumab, nivolumab), PD-L1 inhibitors (atezolizumab, avelumab, durvalumab), CTLA-4 inhibitor (ipilimumab) 4 Colitis symptoms include abdominal pain, rectal bleeding, and blood or mucus in stools 5 Refer to Appendix A for Modified Common Terminology Criteria for Adverse Events (CTCAE) 6 Fecal CMV PCR has low sensitivity and poor negative predictive value for the diagnosis of CMV colitis. Consider early colonoscopy in Continued on next page immunosuppressed patients to exclude CMV colitis and perform colonoscopy in patient with positive fecal CMV by PCR. 7 Screening tests include HIV antibody; T-spot tuberculosis; hepatitis A, B and C panel; and urine Histoplasma antigen Department of Clinical Effectiveness V2 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Evaluation and Management of Suspected Immune-Mediated Page 2 of 10 Colitis/Diarrhea Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. GENERAL EVALUATION - continued PRESENTATION ASSESSMENT ENDOSCOPY FINDINGS Low-risk features: ● Normal colon appearance and normal histology A ● Consult GI Moderate-risk features: 2 3 ● Full colonoscopy and biopsy ● Normal colon appearance with 2,4 3 ● Consider EGD and biopsy pathology showing inflammation ● Focal erythema, friability, or loss of vascularity For management of lower GI Yes ● Small ulcer < 1 cm, shallow toxicity/colitis, see Page 3 ulcer < 2 mm, and/or number of Is the CT abdomen ulcers < 3 positive for colitis/ Other causes(s) for ● No infection identified on biopsy colitis excluded enteritis or are there positive inflammatory High-risk features: markers1? ● Large ulcer ≥ 1 cm, deep No ulcer ≥ 2 mm, and/or number of ulcers ≥ 3 ● Extensive inflammation beyond left colon ● No infection identified on biopsy EGD results with confirmed For upper GI management, inflammation to stomach and see Page 6 Refer to assessment and treatment duodenum EGD = esophagogastroduodenoscopy of diarrhea on Page 4 1 Stool: lactoferrin and calprotectin; blood: ESR and CRP 2 Perform colonoscopy and EGD only if ANC greater than 0.5 K/microliter 3 Examine biopsies for the presence of CMV and other opportunistic infections in immunosuppressed patients 4 Order EGD if there are signs and symptoms of concurrent nausea/vomiting and/or epigastric pain Department of Clinical Effectiveness V2 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Evaluation and Management of Suspected Immune-Mediated Page 3 of 10 Colitis/Diarrhea Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. LOWER GI/COLITIS MANAGEMENT ENDOSCOPY FINDINGS Resume immunotherapy (PD-1 or PD-L1) 1 ● Corticosteroid with taper for total Yes after completion of corticosteroids Clinical follow-up Clinical Low-risk treatment duration less than 30 days ● If refractory to corticosteroids after for recurrent remission features achieved? ● Consider longer duration of infliximab or vedolizumab 3 days, consider one dose of clinical symptoms ● Consider fecal microbiota transplant (FMT) infliximab or vedolizumab No ● Consider repeat colonoscopy if colitis symptoms develop (for endoscopy findings and subsequent management, see Page 2) ● Continue infliximab or vedolizumab until resolution of inflammation on repeat endoscopy 4 ● Resume immunotherapy (PD-1 or Yes PD -L1) after improvement of Symptom mucosal inflammation confirmed improvement? Residual Yes by repeat endoscopy inflammation No seen on 2 Repeat ● Corticosteroids and colonoscopy3 Yes colonoscopy? No ● Start infliximab or Moderate Response vedolizumab within after 3 doses of or high-risk seen on one week of infliximab or features colonoscopy? corticosteroid vedolizumab (8-10 weeks Discontinue infliximab or initiation No ● Consider repeat GI Multiplex after initiation) vedolizumab if imunotherapy is not resumed4 PCR panel if more than 1 week after first test ● Consider FMT or ● Consult surgery 1 May consider budesonide as an additional option 2 Start steroid taper over 2 weeks after starting infliximab or vedolizumab (total corticosteroid treatment duration should be less than 30 days) 3 Consider early repeat colonoscopy after 2 doses of infliximab or vedolizumab if symptoms persist 4 If resuming immunotherapy, continue long-term vedolizumab concurrently Department of Clinical Effectiveness V2 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Evaluation and Management of Suspected Immune-Mediated Page 4 of 10 Colitis/Diarrhea Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. DIARRHEA MANAGEMENT PRESENTATION ASSESSMENT/TREATMENT ● Consider GI infection evaluation (GI Multiplex Resume previous immunotherapy, if held PCR panel and fecal CMV PCR3) Yes ● Consider holding immunotherapy temporarily Improvement Mild diarrhea 4 2 ● Loperamide or diphenoxylate/atropine seen within (Grade 1) ● Consider mesalamine 2.4-4.8 grams/day one week? ● Encourage hydration (2-3 liters per day) No Hold immunotherapy (if not already held) ● Initiate bland diet if severity progresses to Grade 2 diarrhea (see moderate diarrhea management below) Diarrhea without signs or symptoms 1 Hold immunotherapy and order the following: of colitis 3 ● GI Multiplex PCR panel and fecal CMV PCR While test results are pending: ● Initiate appropriate therapy ● Laboratory evaluation: CBC, CMP, and ANA ● Encourage hydration (2-3 liters ● Consider Infectious Diseases ● Inflammatory blood markers: ESR and CRP per day) Yes and/or GI consult as appropriate Moderate and ● Inflammatory stool markers: lactoferrin and ● Initiate bland diet Alternate severe diarrhea calprotectin ● Consider mesalamine causes(s) of (Grade 2 and ● Fecal pancreatic elastase to rule out exocrine diarrhea 2 2.4-4.8 grams/day until culture above) pancreatic insufficiency 6 found? No results return ● Total IgA and tissue transglutaminase (tTG) Treat as non-infectious ● Consider hospitalization if IgA to rule out celiac disease colitis (see Box A on Page 2) 5 inadequate hydration orally ● Screening tests , if not drawn within the past 6-12 months 1 Colitis symptoms include abdominal pain, rectal bleeding, and blood or mucus in stools 2 Refer to Appendix A for Modified Common Terminology Criteria