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

Abstract

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.

Keywords: CTLA-4 antigen; immunotherapy; inflammation; programmed cell death 1 receptor.

Figure 1

Time from the commencement of immunotherapy to the onset of symptoms of colitis in weeks with median and confidence intervals. Time to colitis by immunotherapy regimen (IPI +PD1 in blue vs PD1 in red; p=<0.001). PD1, programmed cell death protein 1; IPI, ipilimumab.

Figure 2

Representative H&E stained sections demonstrating increased different cellular infiltrates in colitis patients treated with monotherapy and combined immunotherapy (IPI+PD1). Representative H&E sections demonstrating increased different cellular infiltrates in colitis patients treated with monotherapy and combined immunotherapy. (A and B) Histopathology image of colonic biopsy of patient treated with anti-PD1 showing a diffuse chronic inflammatory infiltrate within the lamina propria (blue arrow) and an increase in lymphocytes with the surface epithelium (black arrow). A. H&E ×10; B. H&E ×20. (C and D) Histopathology image of colonic biopsy of patient treated with anti-PD1 and anti-CTLA-4 showing a diffuse infiltration of neutrophils within the lamina propria with numerous neutrophilic crypt abscesses (black arrow) and foci of cryptitis (blue arrow). C. H&E ×10; D. H&E ×20. CTLA-4, cytotoxicT-lymphocyte-associated protein 4; PD1, programmed cell death protein 1, IPI, ipilimumab

Figure 3

Kaplan-Meier survival curve stratified by immunotherapy treatment type (IPI+PD1 vs monotherapy with PD1/ipilimumab) and colitis management type (steroid sensitive vs infliximab sensitive vs infliximab refractory) for PFS (A and B) and OS (C and D) (patients with advanced melanoma) and RFS (E and F) (patients receiving adjuvant treatment). (A) PFS by immunotherapy treatment in patients with advanced melanoma (unresectable IIIC/IV). (B) PFS by colitis management type in advanced melanoma patients (unresectable IIIC/IV). (C) OS by immunotherapy treatment type in patients with advanced melanoma (unresectable IIIC/IV). (D) OS by colitis management type in patients with advanced melanoma (unresectable IIIC/IV). (E) RFS by immunotherapy treatment type in patients receiving adjuvant treatment. (F) RFS by colitis management type in patients receiving adjuvant treatment. OS, overall survival; PD1, programmed cell death protein 1; PFS, progression-free survival; RFS, recurrence-free survival.