Calcineurin inhibitors in steroid and anti-TNF-alpha refractory immune checkpoint inhibitor colitis.

BACKGROUND AND AIM: Immune checkpoint inhibitor (ICI) colitis is an increasingly common problem encountered as the use of checkpoint inhibitors (CPIs) grows in the management of cancers. Corticosteroids and tumour necrosis factor (TNF)-alpha inhibitors are widely recommended in the management of ICI colitis; however, the experience is limited when patients are refractory. Different authors have reported success with vedolizumab, mycophenolate, and cyclosporine. This case series describes our experience with calcineurin inhibitors in the management of corticosteroid and anti-TNF-alpha refractory ICI colitis. METHODS: Data from electronic medical records were identified and reviewed retrospectively from a cohort of patients treated at a single oncology center. All patients who were identified between March 2018 and May 2020 with ICI colitis refractory to treatment with infliximab and corticosteroids were included. RESULTS: There were 11 patients who developed ICI colitis after receiving CPIs for advanced melanoma and required rescue therapy with either cyclosporine or tacrolimus after treatment failure of infliximab. Median age was 53 (±8.48) years, with nine patients (81%) receiving combination Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) / programmed cell death protein 1 (PD-1) immunotherapy. Median time after first CPI infusion to ICI colitis was 4.43 (±19.53) weeks. The median time from onset of symptoms to commencement of rescue therapy with calcineurin inhibitors was 70 days (±66.06). Eight of the 11 patients (72.7%) responded to calcineurin inhibition. In patients who responded, calcineurin inhibitors were continued for a median of 54 (±28.96) days. CONCLUSION: The calcineurin inhibitors cyclosporine and tacrolimus appear to be a safe and effective option for the management of patients with infliximab-refractory ICI colitis. The therapeutic benefit is observed rapidly, and adverse effects appear to be limited with close monitoring.

Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab.

BACKGROUND: Colitis is one of the common immune-related adverse events that leads to morbidity and treatment discontinuation of immunotherapy. The clinical presentation, endoscopic and histopathological features and best management of this toxicity are not well defined. PATIENTS AND METHODS: Patients with metastatic melanoma who received immunotherapy (programmed cell death protein 1 (PD1) antibodies, alone or in combination with a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (PD1 +CTLA-4)) and who developed clinically significant colitis (requiring systemic corticosteroids) were identified retrospectively from two academic centers. Clinical data were collected for all patients; endoscopic and histopathological data were examined in a subset. RESULTS: From May 2013 to May 2019, 118/1507 (7.8%) patients developed significant colitis; 80/553 (14.5%) after PD1+CTLA-4, 35/1000 (3.5%) PD1 alone, and three patients after Ipilimumab (IPI) alone. Combination therapy-induced colitis was more frequent (14.5% vs 3.5% in PD1 alone, p=<0.0001), had an earlier onset (6.3 weeks vs 25.7 weeks, p=<0.001), was more severe (grade 3/4 69% vs 31%, p=<0.001), and are more likely to require higher doses of steroids (91% vs 74%, p=0.01) than PD1 colitis. Among all patients treated with steroids (N=114), 54 (47%) responded and required no further therapy (steroid sensitive), 47 patients (41%) responded to infliximab (infliximab sensitive), and 13 (11%) were infliximab refractory and needed further immunosuppressive drugs. Infliximab-refractory patients all had onset within 4 weeks of immunotherapy commencement and were more likely to have an underlying autoimmune disease, have higher grade colitis, and require longer immunosuppression, yet had similar response and survival than other patients with colitis. Of 43 (37%) patients re-resumed treatment with PD1 monotherapy after colitis resolution, 16 (37%) of whom developed recurrent colitis. Endoscopic and histopathologic data were available for 64 patients. Most had left-sided colitis, with an increase in chronic inflammatory cells and neutrophils within the lamina propria, an increase in neutrophils in the surface epithelium, without increased lymphocytes or increased eosinophils. Infliximab-refractory colitis had a trend towards more confluent pancolitis with edema, erythema, ulceration, and absent vascularity with neutrophilic infiltration and erosion. CONCLUSION: Clinically significant colitis varies in presentation, response to immunosuppression, and endoscopic/histologic features depending on the immunotherapy type. Infliximab-refractory colitis occurs early, is often high grade, and has adverse endoscopic and histopathologic features.

When to use biological agents in inflammatory bowel disease.

The use of biological agents in inflammatory bowel diseases across the Asia-Pacific region is increasing. As new molecules and targets are identified, knowledge regarding the indications, utility, optimization and adverse effects of biological agents grows. Careful patient selection, attention to communication and patient education will maximize the benefit of these drugs. Tertiary referral centers with specific interest in inflammatory bowel diseases and experience play an important role in their use. There is enormous opportunity for patients to benefit from biological agents in the therapy of Crohn's disease and ulcerative colitis. Use of these agents has been studied across a variety of indications and populations, and at different stages in the disease course. Failure to respond or loss of response can result from different causes, and can be medically managed in many cases. More research on the pleiotropic effects, safety of biological agents and biomarkers in the prediction of response will provide a sounder basis for individually directing therapy. Adverse events such as opportunistic infection and malignancy can occur, and screening prior to therapy and discussion on risk-benefit of the various management options are important. Cost of these medications especially with maintenance therapy remains an important issue in many Asia-Pacific countries. New and more specific agents will better target therapy and minimize adverse events.