Evaluation and Management of Suspected Immune-Mediated

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 ● Consider longer duration of infliximab or vedolizumab 3 days, consider one dose of clinical symptoms achieved? ● 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 2.4-4.8 grams/day until culture diarrhea above)2 pancreatic insufficiency No results return6 found? ● 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 for Adverse Events (CTCAE) 3 Fecal CMV PCR has low sensitivity and poor negative predictive value for the diagnosis of CMV colitis. Consider early colonoscopy in immunosuppressed patients to exclude CMV colitis and perform colonoscopy in patients with positive fecal CMV by PCR. 4 Consider anti-motility agents only if non-invasive pathogens have been excluded 5 Screening tests include HIV antibody; T-spot tuberculosis; hepatitis A, B and C panel; and urine Histoplasma antigen 6 If cultures return negative and/or no improvement is seen after 2 days of treatment, discontinue mesalamine and consider starting corticosteroids. If patient has symptom improvement with mesalamine, continue treatment regardless of culture results. 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 5 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. RECURRENCE MANAGEMENT

ASSESSMENT TREATMENT

Hold immunotherapy and order the following: 2 ● GI Multiplex PCR panel and fecal CMV PCR ● Laboratory evaluation: CBC, CMP, amylase, and lipase ● Initiate appropriate therapy ● Inflammatory blood markers: ESR and CRP ● Consider Infectious Diseases and/or GI consult as appropriate ● Inflammatory stool markers: lactoferrin and Yes Recurrent colitis/diarrhea calprotectin Alternate (Grade 2 and above)1 after ● Fecal pancreatic elastase to rule out exocrine cause(s) of completion of immunotherapy pancreatic insufficiency colitis/diarrhea toxicity treatment Optional workup: found? No ● Consider infectious workup for non-GI organs For endoscopy findings and Colonoscopy or flex if there is fever or symptoms suggesting subsequent management, individual organ involvement sigmoidoscopy4 with biopsy 3 see Page 2 ● Screening tests , if not drawn within the past 6-12 months ● CT abdomen with oral and IV contrast

1 Refer to Appendix A for Modified Common Terminology Criteria for Adverse Events (CTCAE) 2 Fecal CMV PCR has low sensitivity and poor negative predictive value for the diagnosis of CMV colitis. Consider early colonoscopy in immunosuppressed patients to exclude CMV colitis and perform colonoscopy in patients with positive fecal CMV by PCR. 3 Screening tests include HIV antibody; T-spot tuberculosi; hepatitis A, B and C panel; and urine Histoplasma antigen 4 If initial colonoscopy confirmed left colon involvement, then consider flex sigmoidoscopy on follow-up

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 6 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. UPPER GI MANAGEMENT

ASSESSMENT/TREATMENT

● Continue PPI treatment ● Address factors contributing to inflammation ● Resume immunotherapy, if held ● Proton pump inhibitor (PPI) Yes for 2 weeks trial and EGD results with ● Rule out other factors for Response confirmed inflammation inflammation (i.e., infection, to PPI and other risk Follow-up as to stomach and recent NSAID use, or factors present? clinically indicated duodenum long-term smoking) ● Consider temporary hold of No immunotherapy ● Sufficient corticosteroid course to achieve symptom relief followed by taper for total treatment duration less than 30 days ● Re-assess if symptoms recur

NSAID = non-steroidal anti-inflammatory drugs

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 7 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.

APPENDIX A: Modified1 Common Terminology Criteria for Adverse Events (CTCAE) Gastrointestinal Disorders

Adverse Effect Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Increase of less Increase of 4-6 stools Increase of greater Life-threatening Death Diarrhea than 4 stools per per day over than 7 stools per consequences; day over baseline; baseline; moderate day over baseline; urgent intervention mild increase in increase in ostomy hospitalization indicated ostomy output output compared to indicated; severe compared to baseline; limiting increase in ostomy baseline instrumental output compared to activities of daily baseline; limiting living (ADL) self-care ADL

Colitis Asymptomatic; Abdominal Severe abdominal Life-threatening Death clinical or pain; mucus or pain; peritoneal consequences; diagnostic blood in stool signs urgent intervention observations only; indicated intervention not indicated

1 Modified version includes elements of version 4 and version 5

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 8 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.