Outcomes of Immune Checkpoint Inhibitor-Mediated Colitis: Multicenter Cohort Study

Title from PDF of title page viewed June 6, 2022VitaIncludes bibliographical references (pages 39-43)Thesis (M.S.)--School of Medicine. University of Missouri--Kansas City, 2022Thesis advisor: Monica GaddisImmune checkpoint inhibitor (ICI)-mediated colitis (IMC) is a common and serious toxicity. Multiple reports have described the clinical presentation and course of IMC based on limited data. This was a collaborative effort from several cancer institutes to investigate features and outcomes of IMC. This was a retrospective, cohort study of patients who received ICI and developed endoscopically/histologically confirmed IMC between 1/1/2011 and 12/31/2019. Multivariate logistic regression analyses were conducted to assess predictors of IMC recurrence and long duration of corticosteroids (> 60 days). A total of 674 patients were included. 383 patients were males (56.8%). Median age was 63 years. Melanoma was the most common cancer type (48.4%). Most patients (53.1%) received CTLA-4 inhibitor, as monotherapy or in combination with PD-(L)-1. Median time from ICI therapy to IMC was 61.5 days (31.8-126). IMC was grade 2 in 475 patients (71.3%), grade 3 in 177 (26.6%), and grade 4 in 14 (2.1%). On endoscopy, 153 patients (22.7%) had mucosal ulceration, 130 of patients had severe features (deep, large, or multiple ulcers); 336 patients (49.9%) had non-ulcerative inflammation. Most patients were admitted to the hospital for management of IMC (64.9%). Fifteen patients (2.5%) needed ICU-level of care. Corticosteroids were given to 576 patients (85.5%). Median length of corticosteroid therapy was 52 days. TNF inhibitors were given to 244 patients (36.2%). Ninety patients (13.4%) received vedolizumab. After resolution of symptoms, 201 patients (29.8%) had recurrent IMC. Predictors of IMC recurrence were days of hospitalization (P=0.003) , grade 4 IMC (P=0.001), and use of TNF inhibitor or vedolizumab (P=0.003). Factors associated with long (> 60 days) corticosteroid therapy were grade 3 IMC (P=0.049) and reception of infliximab or vedolizumab (P=0.044). Sixteen patients (2.4%) had colonic perforation, 7 of them underwent surgical resection of a part of the colon. No IMC-related death was recorded. In conclusion, IMC can lead to colonic perforation requiring surgical intervention and ICU admission. Higher grades of IMC or diarrhea and the use of TNF inhibitors or vedolizumab were associated with worse IMC outcomes, and therefore, patients with these features should be monitored closely and treated aggressively early in the course.Introduction -- Review of literature -- Methodology -- Results -- Discussion -- Appendi

Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: A United States multicentre study

Background Limited data exist on the burden and features of non‐cirrhotic hepatocellular carcinoma (HCC) in the United States. Aim To evaluate characteristics, aetiologies, trends and outcomes of non‐cirrhotic HCC from 2000 to 2014 at five large US centres Methods Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. Results Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non‐cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P < .001 for all). Among non‐cirrhotic patients, non‐alcoholic fatty liver disease (NAFLD) was the most common liver disease (26.3%), followed by hepatitis C virus (HCV) (12.1%) and hepatitis B virus (HBV) (10%) infections. As of 2014, there was increased percentage of cirrhotic HCC and a decline in non‐cirrhotic HCC mainly due to significant annual increases in cirrhotic HCC due to HCV (0.96% [P < .0001]) and NAFLD (0.66% [P = .003]). Patients with non‐cirrhotic HCC had larger tumours (8.9 vs 5.3 cm), were less frequently within Milan criteria (15% vs 39%), more frequently underwent resection (43.6% vs 8%) (P < .001 for all) and had better overall survival than cirrhotic HCC patients (median 1.8 vs 1.3 years, P = .004). Conclusions Nearly 12% of HCCs occurred in patients without underlying cirrhosis. NAFLD was the most common liver disease in these patients. During the study, the frequency of non‐cirrhotic HCC decreased, whereas that of cirrhotic HCC increased. Although non‐cirrhotic patients presented with more advanced HCC, their survival was better

Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis

PURPOSE: Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption. METHODS: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. RESULTS: Of the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019). CONCLUSION: One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-

Microbiome alteration Via Fecal Microbiota Transplantation Is Effective For Refractory Immune Checkpoint inhibitor-induced Colitis

Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 1

Vedolizumab Achieved Clinical and Histologic Remission in a Patient with Lung Cancer Who Had a Steroid-Refractory Upper Gastrointestinal Injury Due to Nivolumab Treatment

Immune checkpoint inhibitors (ICIs) have emerged as a novel therapeutic class for various malignancies. Their immune upregulation promotes significant anti-tumor effect, but simultaneously, can also result in treatment-limiting immune-related adverse events (irAEs). The data on upper gastrointestinal (GI) tract irAEs are sparse. We herein describe a case of steroid-dependent upper GI toxicity with nivolumab (an anti-programmed death [PD] protein-1) that achieved clinical and histological remission with vedolizumab treatment (a GI tract targeted anti-integrin antibody). A 65-year-old male patient with progressive lung cancer was treated with nivolumab and following 16 cycles, developed severe nausea, vomiting, and epigastric abdominal cramps requiring five hospitalizations. His initial esophagogastroduodenoscopy (EGD) showed active inflammation in both the stomach and duodenum. Nivolumab was discontinued, but despite treatment with multiple steroid courses, his symptoms always recurred during prednisone taper. Clinical remission was ultimately achieved with vedolizumab. His last EGD after five infusions of vedolizumab demonstrated resolution of inflammation. His lung cancer has since relapsed and the treatment plan was to resume nivolumab concurrently with vedolizumab. In conclusion, ICIs, such as nivolumab, have emerged as therapy for various malignancies. Their use can be associated with various irAEs including the upper GI adverse events which is uncommon. This case scenario showed that vedolizumab can provide a steroid-sparing therapeutic effect to achieve remission of upper GI irAEs even in cases where multiple steroid courses have failed