title: Ipilimumab-induced toxicities and the gastroenterologist.
abstract: Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognized to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune-related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1 mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid-refractory hepatitis and infliximab in the management of corticosteroid-refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab-induced irAEs. Therefore, additional immune-modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab-induced hepatitis was successfully treated with high-dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab-induced colitis, one patient had satisfactory resolution of his colitis with high-dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab-induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high-dose steroids, MMF, azathioprine and calcineurin inhibitors.
authors: A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors: Robert
authors: R
authors: Cheng
authors: Adam
authors: A
authors: Cooper
authors: James
authors: J
authors: Kench
authors: Geoff
authors: G
authors: Watson
authors: William
authors: W
authors: Bye
authors: Catriona
authors: C
authors: McNeil
authors: Nicholas
authors: N
authors: Shackel
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D001379:Azathioprine / Q000008:administration & dosage; D065095:Calcineurin Inhibitors / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D000069285:Infliximab / Q000008:administration & dosage; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary*; D008775:Methylprednisolone / Q000008:administration & dosage; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D010348:Patient Care Team; D011239:Prednisolone / Q000008:administration & dosage; D020551:Pulse Therapy, Drug
chemical_list: D000911:Antibodies, Monoclonal; D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000074324:Ipilimumab; D011239:Prednisolone; D000069285:Infliximab; D009173:Mycophenolic Acid; D001379:Azathioprine; D008775:Methylprednisolone
keywords: CTLA-4 antibody; colitis; hepatitis; immunotherapy; ipilimumab; melanoma