Faisal Ali

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.

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.

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.