Vitiligo-Like Depigmentation in Patients With Stage III-IV Melanoma Receiving Immunotherapy and Its Association With Survival: A Systematic Review and Meta-Analysis Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. Published online ahead of print at www.jco.org on January 20, 2015. Supported by Grant No. UVA2009-4378 from the Dutch Cancer Society (H.-E.T.). Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Hansje-Eva Teulings, MD, Department of Dermatol- ogy, PO Box 22660, 1100DD Amster- dam, the Netherlands; e-mail: h.e.teulings@amc.uva.nl. © 2015 by American Society of Clinical Oncology 0732-183X/15/3399-1/$20.00 DOI: 10.1200/JCO.2014.57.4756 A B S T R A C T Purpose Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival. Methods We systemically searched and selected all studies on melanoma immunotherapy that reported on autoimmune toxicity and/or vitiligo between 1995 and 2013. Methodologic quality of each study was appraised using adapted criteria for systematic reviews in prognostic studies. Random-effect models were used to calculate summary estimates of the cumulative incidence of vitiligo-like depigmentation across studies. The prognostic value of vitiligo-like depigmentation on survival outcome was assessed using random-effects Cox regression survival analyses. Results One hundred thirty-seven studies were identified comprising 139 treatment arms (11 general immune stimulation, 84 vaccine, 28 antibody-based, and 16 adoptive transfer) including a total of 5,737 patients. The overall cumulative incidence of vitiligo was 3.4% (95% CI, 2.5% to 4.5%). In 27 studies reporting individual patient data, vitiligo development was significantly associated with both progression-free- survival (hazard ratio [HR], 0.51; 95% CI, 0.32 to 0.82; P  .005) and overall survival (HR, 0.25; 95% CI, 0.10 to 0.61; P  .003), indicating that these patients have two to four times less risk of disease progression and death, respectively, compared with patients without vitiligo development. Conclusion Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival J Clin Oncol 33. © 2015 by American Society of Clinical Oncology INTRODUCTION Melanoma immunotherapy studies have shown variable success rates in inducing effective anti- melanoma immune responses. The occurrence of immune-related adverse effects after melanoma im- munotherapy has been associated with increased clinical efficacy. 1-6 Vitiligo-like depigmentation, also referred to as vitiligo, is a relatively harmless type of autoimmunity that can occur in patients with melanoma spontaneously or on immunother- apy. The depigmentation results from strong anti- melanoma immunity that also targets healthy melanocytes, as a result of shared expression of me- lanocyte differentiation antigens. The incidence of depigmentation in patients with melanoma varies largely between immunotherapy studies. 7-10 A large, prospective, hospital-based, observational study showed a cumulative incidence of 2.8% of melanoma-associated vitiligo in 2,954 patients with melanoma of different stages regardless of treat- ment. 11 Importantly, vitiligo development in pa- tients with stage III and IV melanoma was associated with tumor regression and prolonged survival in individual studies. 5,7,8,11-14 However, it is not clear to what extent these results can be extrapolated to all immunotherapy studies. Also, it is currently difficult to predict which patients respond to immunothera- peutic treatment. Present prognostic (bio)markers in melanoma are based on the American Joint JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E © 2015 by American Society of Clinical Oncology 1 http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.57.4756 The latest version is at Published Ahead of Print on January 20, 2015 as 10.1200/JCO.2014.57.4756 Copyright 2015 by American Society of Clinical Oncology 145.117.227.11 Information downloaded from jco.ascopubs.org and provided by at Universiteit van Amsterdam on January 21, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved.