MANAGEMENT OF IMMUNOTHERAPY RELATED GI AND HEPATIC ADVERSE EVENTS Wai K. Leung Li Shu Fan Medical Foundation Professor in Gastroenterology Associate Dean (Human Capital), LKS Faculty of Medicine, University of Hong Kong Deputy Director, Integrated Endoscopy Centre, Queen Mary Hospital, Hong Kong
IMMUNOTHERAPY RELATED GI AND LIVER ADVERSE EVENTS 11 RCTs involving 5307 patients Risk ratios for combination therapy were: all-grade diarrhea: 1.95 (95% CI 1.54, 2.46; P < 0.00001) all-grade colitis: 4.45 (95% CI 3.04, 6.51; P < 0.00001). all-grade increased AST: 3.87 (95% CI 2.74, 5.47; P < 0.00001) all-grade increased ALT: 4.29 (95% CI 3.05, 6.04; P < 0.00001) Zhang B et al. Int Immunopharmacol 2018
DIARRHEA AND COLITIS Usually occur within 6wk of starting therapy Median time to onset of diarrhea 5-8 wk after ipilimimab, 3-6 mths after anti-pd-1 Higher for CTLA-4 than PD-1 receptor inhibitors. Incidence of grade ¾ colitis is 7% and 1.8%, respectively. Perforation has been reported, particularly after CTLA-4 inhibitors
CTLA-4 VS ANTI-PD-1 Khoja L et al. Ann Oncol 2017
COLITIS IN PATIENTS TREATED WITH ANTI- PD1 Baxi S et al. BMJ 2018
NO INCREASE IN DIARRHEA Baxi S et al. BMJ 2018
DIARRHEA GRADING: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) V.4 Grade 1: increase of <4 stools per day over baseline. Grade 2: increase of 4 6 stools per day over baseline. Grade 3: increase of 7 or more stools per day over baseline, incontinence, hospitalisation indicated, limiting self-care activities of daily living. Grade 4: life-threatening consequences, urgent intervention indicated. Grade 5: death
COLITIS GRADING: CTCAE V.4 Grade 1: asymptomatic, clinical or diagnostic observations only, intervention not indicated. Grade 2: abdominal pain, mucus or blood in stool. Grade 3: severe abdominal pain, change in bowel habits, medical intervention indicated, peritoneal signs. Grade 4: life-threatening consequences, urgent intervention indicated. Grade 5: death
MANAGEMENT Exclude infections (CMV, Cl. difficile, etc) Grade 1 Symptomatic Rx Grade 2 Withhold immunotherapy, anti-diarrheal agents Consider steroid in persistent symptoms. Grade 3-4 Stop immunotherapy Start systemic steroid Infliximab (anti-tnf) in severe cases
TREATMENT FOR COLITIS Cortisocteroid Budesonide (9mg) can also be used in mild case Severe case or not responding to budesonide, oral prednisolone at 1-2mg/kg/day or IV methylprednisolone up to 2mg/kg twice a day Infliximab 5mg/kg every 2 wk
ENDOSCOPY FOR DIARRHEA Only recommended for persistent grade 2 or above diarrhea since it seldom affect management CT showed mild diffuse bowel thickening Can range from normal endoscopic appearance to severe inflammatory changes with exudates, granularity, erythema, loss of vascularity and erosions/ulcers Biopsy recommended in all cases Usually pancolitis, and minority of left side colitis
ENDOSCOPIC APPEARANCES OF COLITIS 42 (68%) had a pancolitis ( 3 affected segments). Ulcers were seen in 32% of endoscopies. There was no significant correlation between the grade of diarrhoea at presentation and endoscopic severity scores Geukes Foppen MH et al. ESMO Open 2018
HISTOLOGICAL FEATURES Autoimmune-like colopathy in CTLA-4 inhibitors Dense, predominantly lymphocytic infiltrate in the lamina propria along with frequent plasma cells and eosinophils Neutrophilic inflammation is commonly seen, including neutrophilic cryptitis and crypt microabscesses, as well as increased crypt epithelial apoptosis Variable increase in intraepithelial lymphocytes (IELs) In most studies, features of chronicity are typically absent. Granulomas are absent. Anti-PD-1-induced colitis increased apoptosis and crypt atrophy/dropout active mucosal injury, including neutrophilic crypt microabscesses and cryptitis, Granulomas associated with ruptured crypts are seen in 18% of biopsies. Chronicity can be present
HISTOLOGICAL FEATURES OF COLITIS Lymphocytic colitis increased apoptosis Karamchandani DM, J Clin Pathol 2018
Friedman CF, et al. JAMA Oncol 2016
CYCLOSPORINE FOR REFRACTORY CASE Cyclosporine 50mg oral after failure of steroid and infliximab Iyoda T, et al. Am J Case Rep 2018
VEDOLIZUMAB 7 patients with metastatic melanoma or lung cancer, treated with vedolizumab for ipilimumab- or nivolumab-induced enterocolitis all patients but one experienced steroid-free enterocolitis remission, with normalized fecal calprotectin Median 56 days after vedolizumab Berggvist V et al. Cancer Immunol Immunother 2017
OUTCOMES OF DIARRHEA/COLITIS Development of diarrhea and/or colitis during use of 1 checkpoint inhibitor does not necessarily prohibit the use of another Mortality associated with colitis is rare No effective prevention
HEPATIC ADVERSE EVENTS Less frequent than GI adverse events 3-10% of patients More frequently with CTLA-4 blocking antibodies and combination of both Asymptomatic increase in AST and ALT Most often 8-12 wk after starting therapy but may occur at any time Imaging usually normal. Severe case show conspicuous periportal echogenicity, edema of GB, and even hepatomegaly
HEPATITIS AND ANTI-PD1 Baxi S et al. BMJ 2018
HEPATITIS GRADING: CTCAE V.4 Grade 1: AST or ALT 1 2.5 upper limit of normal (ULN) and/or T-BIL1 1.5 ULN. Grade 2: AST or ALT 2.5 5 ULN and/or T-BIL 1.5 3 ULN. Grade 3: AST or ALT >5 ULN and/or T-BIL >3 ULN. Grade 4: AST or ALT >8 ULN. Grade 5: death.
HISTOLOGICAL FEATURES Anti-CTLA-4 Active panlobular hepatitis with a mixed inflammatory infiltrate consisting predominantly of lymphocytes Centrilobular (zone 3) hepatitis Anti-PD-1 Few reports Predominantly lobular hepatitis with milder portal inflammation
CHECKPOINT INHIBITOR-INDUCED HEPATIC INJURY active panlobular hepatitis Karamchandani DM, J Clin Pathol 2018
DIFFERENTIAL DIAGNOSIS Autoimmune hepatitis ANA, anti-smooth muscle antibody IgG levels Viral hepatitis HBsAg, anti-hbc, anti-hbs Anti-HAV, anti-hev IgM anti-hcv Drug induced liver injury (DILI) Liver biopsy is usually necessary for assessment of disease severity
TREATMENT Discontinuation of immunotherapy Corticosteroid Prednisone 1-2 mg/kg/d Methylprednisolone 0.5-1 mg/kg/d Combination with MMF (500-1000mg every 12h) or Tarcolimus Anti-thymocyte globulin (ATG) in highly refractory case with rapid clinical decompensation May take >1 month to resolve
De Martin E, J Hepatol 2018
TREATMENT De Martin E, J Hepatol 2018
Friedman CF, et al. JAMA Oncol 2016
CONCLUSION CTLA-4 inhibitors tend to have more GI and liver AEs than anti-pd-1 Acute hepatitis resulting from immunotherapy is not common (3.5%) and, in most cases, not severe. Colonoscopy/sigmoidoscopy has limited role on the diagnosis of GI side effects. Liver biopsy would be helpful for the diagnosis and evaluation of the severity of liver injury. The mainstay of irae treatment consists of immunosuppression with corticosteroids or other immunosuppressant agents such as infliximab; most iraes will resolve with appropriate management.