Immune-related adverse events following administration of anti-cytotoxic T-lymphocyte-associated protein-4 drugs: a comprehensive systematic review and meta-analysis

Abstract

Objective:

Administration of drugs targeting anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is often associated with serious immune-related adverse events (irAEs). Here, we performed a comprehensive analysis of organ-specific irAEs and treatment-related hematologic abnormalities and musculoskeletal disorders resulting from anti-CTLA-4 treatment.

Materials and methods:

PubMed, the Cochrane library, Web of Science, and ClinicalTrials.gov were searched for studies between January 1990 and March 2018 reporting AEs associated with anti-CTLA-4 therapies.

Results:

A total of 11 clinical trials with 7,088 patients were included; of these, data were accessible for 10 on ClinicalTrials.gov. Compared with control therapies (placebo, chemotherapy, radiation therapy, or vaccine), anti-CTLA-4 therapies (ipilimumab and tremelimumab) were associated with an increased risk of serious irAEs, predominantly dermatologic (rash: odds ratio [OR] 3.39, P<0.01), gastrointestinal (diarrhea and colitis: OR 6.57 and 14.01, respectively; both P<0.001), endocrine (hypophysitis, hypothyroidism, adrenal insufficiency, and hypopituitarism: OR 4.22, 3.72, 3.77, and 4.73, respectively; all P<0.05), and hepatic (hepatitis, elevated alanine aminotransferase, and elevated aspartate aminotransferase: OR 4.44, 3.28, and 3.12, respectively; all P<0.05). The most common serious organ-specific irAEs were gastrointestinal (diarrhea 9.8% and colitis 5.3%). Although the incidence of selected events was higher in anti-CTLA-4-treated patients, no significant differences were found between anti-CTLA-4 and the control therapies in treatment-related hematologic abnormalities or severe musculoskeletal disorders.

Conclusion:

Anti-CTLA-4 therapies are associated with an increased risk of serious organ-specific irAEs, most frequently involving the gastrointestinal system; however, no increased risk of hematologic abnormalities or severe musculoskeletal disorders was detected compared with other therapies. These results underscore the need for clinical awareness and prompt and effective management of multi-organ irAEs related to anti-CTLA-4 drugs.

Keywords:

• immune-related adverse events
• anti-CTLA-4 drugs
• ipilimumab
• tremelimumab

Acknowledgments

This program was supported by the National Natural Science Foundation of China (Grant No.81300627, No.81702536), Programs from Science and Technology Department of Sichuan Province (Grant No. 2018JY0089 and No. 2018HH0153), the Prostate Cancer Foundation Young Investigator Award 2013, Chengdu Technological Innovation Research and Development Project (Chengdu Science and Technology Bureau, 2018-YFYF-00131-SN), a grant from 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYGD18011), and Young Investigator Award of Sichuan University 2017 (Grant No. 2017SCU04A17). The funders had no role in patient selection, data extraction, statistical analysis or interpretation, writing of this article, or the decision to publish. The authors would like to thank Anne M. O’Rourke, PhD, from Liwen Bianji, Edanz Group China, for editing the English text of a draft of this manuscript.

Abbreviations

IrAEs, immune-related adverse events; Anti-CTLA-4, anti-cytotoxic T-lymphocyte-associated protein-4; ALT, alanine aminotransferase; AST, aspartate aminotransferase; OR, odds ratio; CI, confidence interval; CTCAE, Common Terminology of Clinical Adverse Events; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Supplementary materials

Figure S1 Flow diagram for study selection.

Figure S2 Forest plot of the overall risk of hypopituitarism related to anti-CTLA-4 drugs.

Figure S3 Forest plot of the overall risk of ALT and AST elevation related to anti-CTLA-4 drugs.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Figure S4 Forest plot of the overall risk of Guillain–Barre syndrome related to anti-CTLA-4 drugs.

Author contributions

All authors contributed toward data analysis, drafting and revising the paper, gave final approval of the version to be published and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.