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

Autor:	Nahar KJ; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia., Rawson RV; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia., Ahmed T; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia., Tattersall S; Gastroenterology, Royal North Shore Hospital, St Leonards, New South Wales, Australia., Sandanayake N; Gastroenterology, Royal North Shore Hospital, St Leonards, New South Wales, Australia., Kiely CJ; Gastroenterology, Royal North Shore Hospital, St Leonards, New South Wales, Australia., Lo S; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia., Carlino M; Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia., Palendira U; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia., Scolyer RA; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia., Long GV; Melanoma Institute Australia, North Sydney, New South Wales, Australia.; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.; Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.; Medical Oncology, Mater Hospital, Sydney, New South Wales, Australia., Menzies AM; Melanoma Institute Australia, North Sydney, New South Wales, Australia alexander.menzies@sydney.edu.au.; Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.; Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.; Medical Oncology, Mater Hospital, Sydney, New South Wales, Australia.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2020 Nov; Vol. 8 (2).
DOI:	10.1136/jitc-2020-001488
Abstrakt:	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. Competing Interests: Competing interests: GL is a consultant advisor for Aduro, Amgen, Bristol-Myers Squibb, Mass-Array, Merck, MSD, Novartis, OncoSec Medical, Pierre Fabre, Roche, Q biotics and Sandoz. MC is a consultant advisor for BMS, MSD, Novartis, Roche, Pierre Fabre, Sanofi, Merck Serono, Eisai, Nektar, Ideaya and Q biotics. AM is a consultant advisor to BMS, MSD, Novartis, Roche and Pierre-Fabre. (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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