Immune-Related Adverse Events for GI Toxicity - Colitis

Grades severity of colitis secondary to immune checkpoint inhibitor therapy.

Why Use

ICPi colitis is the most common cause of hospital admissions due to immune related adverse events. This tool aids in the decision to discontinue ICPi, further diagnostic work-up, and immunosuppressant treatment initiation.

When to Use

Adult patients with colitis symptoms that developed while on treatment with immune checkpoint inhibitors including agents against PD-1 (i.e., pembrolizumab, nivolumab), PD-L1 (i.e., atezolizumab, avelumab, durvalumab), or CTLA-4 (i.e., ipilimumab).

Formula

CTCAE for diarrhea Colitis grade Increase of <4 stools per day over baseline; mild increase in ostomy output compared with baseline G1 Increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared with baseline G2 Increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care/activities of daily living G3 Life-threatening consequences; urgent intervention indicated G4 See Next Steps for details on management.

Pearls / Pitfalls

Immune checkpoint inhibitor (ICPi) colitis should be suspected in patients with symptoms of colitis (e.g. change in bowel habits, abdominal pain, blood and mucus in stool, fever, abdominal distension, obstipation, constipation) while on treatment with immune checkpoint inhibitors. May occur at any time during immune checkpoint inhibitor treatment, but is most frequently seen 5-10 weeks following treatment initiation. More frequently seen with anti-CTLA-4 agents, but is also an important adverse event caused by anti-PD-1 and anti-PD-L1 agents. Management of ICPi colitis is based on the grade of colitis.

Management

ASCO guidelines for IRAE - colitis : All patients: Counsel all patients to be aware of and inform their health care provider immediately if they experience any of the following: Abdominal pain, nausea, cramping, blood or mucus in stool, or changes in bowel habits. Fever, abdominal distention, obstipation, or constipation. For grade ≥2, consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD- L1 agents if patient can recover to grade ≤1; concurrent immunosuppressant maintenance therapy should be considered only if clinically indicated in individual cases. Grade 1: Continue ICPi (or, hold temporarily and resume if toxicity does not exceed grade 1). Monitor for dehydration; recommend dietary changes. Facilitate expedited phone contact with patient/caregiver. May obtain GI consult for prolonged grade 1 cases. Grade 2: Should hold immune checkpoint inhibitor until symptoms recover to grade 1; can consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patient can recover to grade ≤1. Concurrent immunosuppressant maintenance therapy (<10 mg prednisone equivalent dose) may be offered only if clinically indicated in individual cases. May include supportive care with medications such as loperamide if infection has been ruled out. Should consult with GI for grade ≥2. Administer corticosteroids, unless diarrhea is transient, starting with an initial dose of 1 mg/kg/day prednisone or equivalent. When symptoms improve to grade ≤1, taper corticosteroids over at least 4-6 weeks before resuming treatment, although resuming treatment while on low-dose corticosteroid may also be an option after an evaluation of the risks and benefits. Esophagogastroduodenoscopy/colonoscopy, endoscopy evaluation should be highly recommended for cases grade ≥2 to stratify for early infliximab treatment based on endoscopic findings and to determine safety of resuming PD-1, PD-L1 therapy. Can consider stool inflammatory markers (lactoferrin and calprotectin) in cases of grade ≥2 to differentiate functional vs inflammatory diarrhea, and use calprotectin to monitor treatment response if provider prefers. Repeat colonoscopy optional for cases of grade ≥2 to monitor disease activity for complete remission, especially if plan to resume ICPi. Grade 3: Should consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patient can recover to grade ≤1. Administer corticosteroids (initial dose of 1–2 mg/kg/day prednisone or equivalent). Consider hospitalization or outpatient facility if dehydration or electrolyte imbalance. If symptoms persist 3–5 days or recur after improvement, consider IV corticosteroid or noncorticosteroid (e.g. infliximab) treatment. Consider colonoscopy if patient on immunosuppression and at risk for opportunistic infections as an independent cause for diarrhea (i.e., CMV colitis) or if on anti-TNF or corticosteroid refractory. Grade 4: Permanently discontinue treatment. Should admit patient when clinically indicated; patients managed as outpatients should be very closely monitored. Administer 1–2 mg/kg/day methylprednisolone or equivalent until symptoms improve to grade 1, and then start taper over 4–6 weeks. Consider early infliximab 5–10 mg/kg if symptoms refractory to corticosteroid within 2–3 days. Consider lower GI endoscopy if symptoms are refractory despite treatment or there is concern of new infections. Additional considerations: Vedolizumab may be considered in patients refractory to infliximab and/or contraindicated to TNF-α blocker. Decision should be made on individual basis from GI and oncology evaluation. This is based on case series showing promising results. Patients with hepatitis and IRAE colitis are rare, and management should include permanently discontinuing immune checkpoint inhibitors and offering other immunosuppressant agents that work systemically for both conditions. Currently, enteritis alone as the cause of diarrhea is uncommon and requires small bowel biopsy to evaluate. It may be managed similar as colitis, including corticosteroid and/or infliximab, etc. See Brahmer 2018 for full ASCO guidelines.

Advice

Grade 1: Further diagnostic work-up not recommended. Grade 2: Further diagnostic work-up is recommended as following: Blood studies: CBC, comprehensive metabolic panel, thyroid-stimulating hormone, erythrocyte sedimentation rate, C-reactive protein. Stool studies: culture, Clostridium difficile, parasite, cytomegalovirus (CMV) or other viral etiology, ova and parasite. Lactoferrin – aids in patient stratification to determine who needs more urgent endoscopy. Calprotectin – aids in follow up of disease activity. Screening for HIV, hepatitis A and B, and blood quantiferon for tuberculosis in patients at high risk for infections – aids in preparation of patients to start infliximab. Consider imaging (i.e., CT scan of abdomen and pelvis and gastrointestinal endoscopy with biopsy) – presence of ulceration can predict corticosteroid refractory disease, which may require early infliximab. Consider repeat endoscopy for patients who do not respond to immunosuppressive agents. Consider repeat endoscopy for disease monitoring when clinically indicated and when planning to resume therapy. Grade 3-4: Above work-up for grade 2 colitis should be immediately completed for grade 3-4 colitis. Consider repeat endoscopy for patients who do not respond to immunosuppressive agents. Consider repeat endoscopy for disease monitoring only when clinically indicated and when planning to resume therapy.