Acute visual loss after ipilimumab treatment for metastatic melanoma

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Abstract

Background

Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs).

Case presentation

Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs.

Conclusions

This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.

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Most cited references 23

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Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

Jedd Wolchok, Bart Neyns, Gerald P. Linette … (2010)

Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Bristol-Myers Squibb. Copyright 2010 Elsevier Ltd. All rights reserved.

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Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.

Kimberly E Beck, Joseph A. Blansfield, Khoi Tran … (2006)

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is an inhibitory receptor on T cells. Knocking out CTLA4 in mice causes lethal lymphoproliferation, and polymorphisms in human CTLA4 are associated with autoimmune disease. Trials of the anti-CTLA4 antibody ipilimumab (MDX-010) have resulted in durable cancer regression and immune-mediated toxicities. A report on the diagnosis, pathology, treatment, clinical outcome, and significance of the immune-mediated enterocolitis seen with ipilimumab is presented. We treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab. The overall objective tumor response rate was 14%. We observed several immune mediated toxicities including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Enterocolitis, defined by grade 3/4 clinical presentation and/or biopsy documentation, was the most common major toxicity (21% of patients). It presented with diarrhea, and biopsies showed both neutrophilic and lymphocytic inflammation. Most patients who developed enterocolitis responded to high-dose systemic corticosteroids. There was no evidence that steroid administration affected tumor responses. Five patients developed perforation or required colectomy. Four other patients with steroid-refractory enterocolitis appeared to respond promptly to tumor necrosis factor alpha blockade with infliximab. Objective tumor response rates in patients with enterocolitis were 36% for MM and 35% for RCC, compared with 11% and 2% in patients without enterocolitis, respectively (P = .0065 for MM and P = .0016 for RCC). CTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients.

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Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.

Gerald Falchook, Karl D Lewis, Jeffrey Infante … (2012)

MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma. We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622. 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%). Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Melissa A. Wilson: Melissa.Wilson@nyumc.org

Kelly Guld: Kelly.Guld@ucsf.edu

Steven Galetta: Steven.Galetta@nyumc.org

Ryan D. Walsh: rdwalsh@mcw.edu

Julia Kharlip: Julia.Kharlip@uphs.upenn.edu

Madhura Tamhankar: Madhura.Tamhankar@uphs.upenn.edu

Suzanne McGettigan: Suzanne.McGettigan@uphs.upenn.edu

Lynn M. Schuchter: Lynn.Schuchter@uphs.upenn.edu

Leslie A. Fecher: 734-615-4762 , LFecher@med.umich.edu

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Title: Journal for Immunotherapy of Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-1426

Publication date (Electronic): 18 October 2016

Publication date PMC-release: 18 October 2016

Publication date Collection: 2016

Volume: 4

Electronic Location Identifier: 66

Affiliations

[1 ]Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA

[2 ]Department of Medicine, University of Pennsylvania, Philadelphia, PA USA

[3 ]Department of Neurology, NYU Langone Medical Center, New York, NY USA

[4 ]Departments of Ophthalmology and Neurology, Medical College of Wisconsin, Milwaukee, WI USA

[5 ]Division of Endocrinology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA

[6 ]Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania Health System, Philadelphia, PA USA

[7 ]Present address: Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY USA

[8 ]Present address: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C366 MIB 1500 E. Medical Center Drive, SPC5848, Ann Arbor, MI 48109 USA

[9 ]Present address: Department of Cardiology, UCSF Medical Center, San Francisco, CA USA

Article

Publisher ID: 170

DOI: 10.1186/s40425-016-0170-9

PMC ID: 5067900

PubMed ID: 27777775

SO-VID: 9c6c408e-24d0-473f-9fd7-e91aa37fd353

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 24 March 2016

Date accepted : 29 September 2016

Custom metadata

Keywords: melanoma,ipilimumab,immune,side effects,optic neuritis,checkpoint inhibitors

Data availability:

Keywords: melanoma, ipilimumab, immune, side effects, optic neuritis, checkpoint inhibitors

Acute visual loss after ipilimumab treatment for metastatic melanoma

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Abstract

Background

Case presentation

Conclusions

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HLA-G and immune tolerance in pregnancy

Most cited references 23

Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.

Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.

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