Hamzah Abu-Sbeih

Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: Retrospective review at MD Anderson

BackgroundImmune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients’ outcomes.MethodsThis retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups.ResultsDiarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (nxa0=u200944) or with infliximab (nxa0=u200935). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (Pxa0<u20090.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (Pxa0=u20090.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; Pxa0=u20090.768). Diarrhea was an independent predictor of a favorable overall survival (Pxa0<u20090.001), irrespective of treatment need (Pxa0=u20090.003). We confirmed the same results in a subgroup analysis for patients with stage IV malignancies only. Patients who received long duration of steroid treatment (>u200930xa0days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, Pxa0=u20090.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, Pxa0=u20090.089).ConclusionsPatients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.

Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis

BackgroundnDiarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients clinical characteristics and outcomes.nnnMethodsnWe retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long-term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves.nnnResultsnMost patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis.nnnConclusionn10.1093/ibd/izy104_video1izy104.video15808053084001.

The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients' outcomes

Background: Immune checkpoint inhibitors (ICPIs) are gaining more popularity as a treatment for advanced cancers. However, immune-related adverse events (irAEs) limit their use. We aimed to assess the impact of irAEs and their treatment on clinical and survival outcomes. Materials and Methods: We retrospectively reviewed records of the patients who received ICPIs between 2011 and 2017. Descriptive analyses were employed to compare different groups. Kaplan–Meier curves and log-rank tests were used to estimate and compare overall survival durations. Results: Of 427 identified patients, 202 (47.3%) had one or more irAEs. Overall, the patients who developed irAEs had better overall survival than did patients with no-irAEs, regardless of immunosuppressant treatment (P < 0.01). Patients with mild irAEs who did not require immunosuppressive treatment had longer overall survival duration than did patients without irAEs (P < 0.01). Patients with three or more irAEs had longer median overall survival compared to patients with two or less irAEs (P = 0.01). Infliximab was associated with shorter duration of steroid use as compared to steroid treatment only (2 months [standard deviation (SD), 8] vs. 4 months [SD, 4]). Steroid treatment for >30 days was associated with higher rate of infections compared to shorter duration (P = 0.03). Conclusion: IrAEs are associated with favorable overall survival, regardless of immunosuppression treatment requirement. IrAEs involving multiple organs appeared to be beneficial for overall survival. Early infliximab use shortens the duration of steroid treatment and therefore balances better cancer outcomes with decreased risk of infection.

Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis

BackgroundImmune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX.MethodsData were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints.ResultsAmong 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; pu2009<u20090.001), median times to diarrhea resolution (3 vs. 9xa0days; pu2009<u20090.001) and to steroid titration (4 vs. 13xa0days; pu2009<u20090.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51xa0days; pu2009=u20090.150) was numerically lower in the IFX group.ConclusionsDespite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.

Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis

BackgroundImmune checkpoint inhibitors (ICPI) are efficacious treatments for advanced malignancies but can result in immune mediated diarrhea and colitis (IDC). Currently, the guidelines for the treatment of IDC depend only on clinical symptoms. Endoscopic and histologic features of such adverse events are not well studied in a manner that can help to gauge treatment plans. We aimed to characterize endoscopic and histologic features of IDC and to assess their association with clinical outcomes.MethodsOur study included patients who had undergone endoscopy for IDC (1/2010 to 3/2018). Patients with GI infection at time of onset were excluded. High-risk endoscopic features were ulcers deeper than 2xa0mm, larger than 1xa0cm, and extensive colonic involvement. Univariate and multivariate logistic regression were performed to assess the association of endoscopic and histological features with clinical outcomes.ResultsA total of 182 patients was included; most were white (92%), males (65%) with a mean age of 60xa0years. Median time from ICPI initiation to IDC was 7xa0weeks. Fifty-three percent had grade 3–4 diarrhea, and 32% grade 3–4 colitis. Forty-nine patients had mucosal ulcerations, 66 non-ulcerative inflammation and 67 normal endoscopy. Calprotectin was higher in patients with ulceration (Pu2009=u20090.04). The sensitivity of lactoferrin to detect histologic and endoscopic inflammation was 90% and 70% respectively. Patients who underwent endoscopy earlier than 7xa0days after IDC onset had shorter duration of IDC symptoms and duration of steroid treatment than those who underwent endoscopy after 7xa0days of IDC onset (Pu2009=u20090.026 and Pu2009=u20090.053, respectively). Patients who underwent endoscopy >u200930xa0days of symptom onset required longer duration of steroids (Pu2009=u20090.02), had more recurrent symptoms (Pu2009< 0.01) and received later infliximab/vedolizumab add-on therapy than did those who underwent endoscopy ≤30xa0days (Pu2009=u20090.03). High-risk features were associated with more frequent (Pu2009=u20090.03) and longer duration (Pu2009=u20090.02) hospitalization and infliximab/vedolizumab requirement (Pu2009< 0.01). Patients with active histological inflammation had more recurrence (Pu2009< 0.01) and repeat endoscopy (Pu2009< 0.01). Repeat endoscopy was required in 47 patients. A multivariate logistic regression revealed that longer ICPI treatment was associated with more frequent hospitalizations (OR 1.00; 95%CI 1.00–1.01; Pu2009< 0.01) and high-risk endoscopic features were associated with the requirement of infliximab/vedolizumab (OR 3.89; 95%CI 1.68–9.01; Pu2009< 0.01).ConclusionHigh risk endoscopic features and active histologic inflammation represent important markers of disease severity with clinical implications and should be used in a timely manner to devise IDC-focused treatment algorithms.

Can Immune Checkpoint Inhibitors Induce Microscopic Colitis or a Brand New Entity

BackgroundnMicroscopic colitis (MC) has been described as 1 pattern of injury in immune checkpoint inhibitor (ICPI)-induced colitis. The main objective of this study was to characterize ICPI-induced MC by exploring the differences in risk factors, colitis treatments, endoscopic features, and clinical outcomes between cancer and noncancer patients with MC with and without exposure to ICPIs.nnnMethodsnA retrospective chart review was conducted among patients diagnosed with MC from our institutional pathology database from January 2012 to January 2018. Patients were categorized into MC in cancer patients with or without ICPI exposure and in noncancer patients. Risk factors (use of tobacco and certain medications), colitis treatments (antidiarrheals and immunosuppressants), endoscopic features (with or without mucosal abnormality), and clinical outcomes (diarrhea recurrence, hospitalization, mortality) were collected and compared among the 3 groups.nnnResultsnOf the 65 eligible patients with MC, 15 cancer patients had exposure to ICPI, 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001).nnnConclusionnThis study suggests that despite some similarities between MC with and without exposure to ICPIs, ICPI-induced MC has a more aggressive disease course that requires more potent immunosuppressive treatment regimens and greater need for hospitalization. 10.1093/ibd/izy240_video1izy240.video15828223597001.