Colitis after checkpoint blockade: A retrospective cohort study of melanoma patients requiring admission for symptom control

Abstract

Background Immune checkpoint inhibitors (CPIs) have revolutionized oncologic therapy but can lead to immune‐related adverse events (irAEs). Corticosteroids are first‐line treatment with escalation to biologic immunosuppression in refractory cases. CPI‐related gastroenterocolitis (GEC) affects 20%‐50% of patients receiving CPIs and can carry significant morbidity and mortality. Severe CPI‐related GEC is not well‐described. We present the clinical characterization of all CPI‐related GEC requiring admission at a single institution. Methods Clinical, laboratory, radiographic, and endoscopic data were extracted from charts of all melanoma patients ≥18 years of age admitted to one institution for CPI‐related GEC, from February 5, 2011 to December 13, 2016. Patients were followed until December 31, 2017 for further admissions. Survival, outcomes, and pharmaceutical‐use analyses were performed. Results Median time‐to‐admission from initial CPI exposure was 73.5 days. Median length of stay was 4.5 days. About 50.0% required second‐line immunosuppression. Readmission for recrudescence occurred in 33.3%. Common Terminology Criteria for Adverse Events (CTCAE) grade was not significantly associated with outcomes. Hypoalbuminemia ( P = 0.005), relative lymphopenia ( P = 0.027), and decreased lactate dehydrogenase ( P = 0.026) were associated with second‐line immunosuppression. There was no difference in progression‐free survival (PFS) or OS ( P = 0.367, 0.400) for second‐line immunosuppression. Subgroup analysis showed that early corticosteroid administration ( P = 0.045) was associated with decreased PFS. Conclusions Severe CPI‐related GEC typically manifests within 3 months of immunotherapy exposure. Rates of second‐line immunosuppression and readmission for recrudescence were high. CTCAE grade did not capture the degree of severity in our cohort. Second‐line immunosuppression was not associated with poorer oncologic outcomes; however, early corticosteroid exposure was associated with decreased PFS. Further investigation is warranted.

Retrospective Analysis of Treatment and Complications of Immune Checkpoint Inhibitor-Associated Colitis: Histological Ulcerations as Potential Predictor for a Steroid-Refractory Disease Course

“…Our results may therefore be biased toward more severe cases, as mild cases of irAEs are usually treated by dermatologists themselves. This might explain the reported severity of symptoms, high CTCAE grades, and the prevalence of complications, as a comparable recent study detected a need for surgery in 3/60 patients (vs. 2/33 patients in our study) [26]. Furthermore, it also explains why such a high number of 22 patients (67%) presented with a steroid-refractory disease course needed additional treatment with infliximab or even surgery.…”

“…Furthermore, it also explains why such a high number of 22 patients (67%) presented with a steroid-refractory disease course needed additional treatment with infliximab or even surgery. And it might also explain why the majority of patients had cancer progression despite severe colitis, which is in contrast to an earlier study investigating the disease course in patients with checkpoint inhibitor-induced colitis [26].…”

Systematic review with meta‐analysis: effectiveness of anti‐inflammatory therapy in immune checkpoint inhibitor‐induced enterocolitis

“…Thirty‐three studies reported outcomes on 1104 checkpoint inhibitor‐induced enterocolitis patients treated with corticosteroids. Just over half of data were contributed by 6 studies; Abu‐Sbeih et al 9 (n = 141), Wang et al, 2019 23 (n = 109), Nahar et al, 2019 24 (n = 106) Foppen et al 10 (n = 92), Spain et al 25 (n = 72) and Hughes et al(II), 2019 28 (n = 57). Reporting of the corticosteroid dose and regimen used was inconsistent and described in 20 studies.…”

“…Most studies incorporated a range of regimens including prednisolone (14 studies), hydrocortisone (3 studies), methylprednisolone (6 studies) and budesonide (5 studies). Three of the 6 largest aforementioned studies provide a more detailed description of the corticosteroid regimen employed, with Hughes et al(II) 28 reporting that 87.5% of patients received at least 1 mg/kg prednisone or equivalent; Foppen et al 10 describing budesonide use in 12 episodes and “high dose corticosteroids” in 92 episodes (32 episodes at a dose of <1 mg/kg, 57 at 1 mg/kg and 3 at >1 mg/kg) and Wang et al 23 reporting that anti‐PD‐1 monotherapy and combination regimen treated patients received a median of 1.0 and 1.5 mg/kg prednisone equivalent respectively.…”

“…Overall, the pooled response to corticosteroids was 59% (95% CI 54-65), which was associated with a high degree of statistically significant heterogeneity between studies (I 2 = 61%, P < 0.001) ( Figure 2A). The median time to response was defined in seven studies, [27][28][29][30][31][32][33] varying between 1 day 27 and 95 29…”