Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis

Abstract

Introduction: Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis.

Methods: We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment.

Results: Twenty-two patients (14 male) with a median age of 64 (range 45-84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD.

Conclusions: Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.

Keywords: Immunotherapy; Inflammation.

Figure 1

Clinical, endoscopic and histological characteristics of 22 patients. Severity of diarrhea (purple bars) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. CTCAE Grade 0: no symptoms of diarrhea. Grade 1: Increase of <4 stools per day over baseline. Grade 2: increase of 4–6 stools per day over baseline; limiting instrumental activities of daily living (ADL). Grade 3: increase of ≥7 stools per day over baseline; hospitalization indicated; limiting self-care ADL. Endscopic severity (brown bars) on baseline endoscopic assessment according to Mayo endoscopy score. Histological features shown in table format with green/yellow/red color scheme denoting severity of findings.

Figure 2

Histological images pretreatment and post-treatment with BD. (A) (Patient 2 pretreatment): increase in chronic inflammatory cells in the lamina propria and neutrophilic infiltrate. Crypt disruption and crypt abscesses. (B) (Patient 2 post-treatment): increase in plasma cells in lamina propria, apoptotic bodies in base of the crypts, no evidence of cryptitis or crpyt abscesses. (C) (Patient 7 pretreatment): congestion in the lamina propria and an increase in chronic inflammatory cells. Occasional apoptotic bodies are seen at the base of the crypt epithelium. (D) (Patient 7 post-treatment): normal large bowel mucosa. BD, beclomethasone dipropionate.

Figure 3

Clinical outcomes after a single course of BD. Shown are proportions of patients achieving a clinical response (left bar—defined as an improvement in diarrhea symptoms), clinical remission (middle bar—defined as a return to baseline stool frequency) and durable remission (right bar—defined as absence of relapse of diarrhea symptoms after treatment cessation). BD, beclomethasone dipropionate.

Figure 4

(A) Time course of clinical relapse after stopping BD in 10 patients who relapsed. (B) Final clinical outcomes following BD therapy. *In seven patients who had further relapses after >1 course of BD, four patients ultimately achieved remission without the need for alternative therapy. One patient was treated with 5-ASA, one patient was treated with MMF and one patient died following peritoneal malignant disease progression. BD, beclomethasone dipropionate; MMF, mycophenolate mofetil.