Clinical Presentation and Prognostic Features in Patients with Immunotherapy-Induced Vitiligo-like Depigmentation: A Monocentric Prospective Observational Study

Abstract

Vitiligo-like depigmentation (VLD) is an immune-related adverse event (irAE) of checkpoint-inhibitor (CPI) treatment, which has previously been associated with a favourable outcome. The aim of this study was to explore clinical, biological and prognostic features of melanoma patients with VLD under CPI-treatment and to explore whether they exhibit a characteristic immune response profile in peripheral blood. Melanoma patients developing VLD under CPI were included in a prospective observational single-center cohort study. We collected and analysed clinical parameters, photographs and serum from 28 VLD patients. They received pembrolizumab (36%), nivolumab (11%), ipilimumab/nivolumab (32%) or clinical trial medications (21%). We performed a high-throughput proteomics assay (Olink), in which we identified a distinct proteomic signature in VLD patients in comparison to non-VLD CPI patients. Our clinical assessments revealed that VLD lesions had a predominantly symmetrical distribution pattern, with mostly smaller “freckle-like” macules and a preferential distribution in UV-exposed areas. Patients with previous targeted therapy showed a significantly longer time lapse between CPI initiation and VLD onset compared to non-pre-treated patients (12.5 vs. 6.25 months). Therapy responders exhibited a distinct proteomic profile when compared with non-responders in VLD such as upregulation of EDAR and downregulation of LAG3. ITGA11 was elevated in the VLD-group when compared to non-VLD-CPI-treated melanoma patients. Our findings demonstrate that on a proteomic level, VLD is characterized by a distinct immune signature when compared to CPI-treated patients without VLD and that therapy responsiveness is reflected by a characteristic immune profile. The pathomechanisms underlying these findings and how they could relate to the antitumoral response in melanoma remain to be elucidated.

Cutaneous Adverse Events of Systemic Melanoma Treatments: A Retrospective Single-Center Analysis

“…These cases are not captured in our analysis, as pruritus alone is not formally a rash and macroscopically unchanged skin would very rarely be biopsied. Furthermore, vitiligo-like depigmentation is described as an on-target effect in patients with melanoma in general and frequently with ICB [ 15 ]. However, we did not include this well-characterized adverse event in our cohort.…”

“…In addition, vitiligo-like depigmentation and alopecia were not considered for this investigation. Vitiligo-like depigmentations have previously been described [ 15 ], and alopecia is not conventionally considered a skin AE. In addition, vitiligo does not require a biopsy for diagnostic purposes.…”

“…Bullous ircAE has a stronger association with PD-1- and PD-L1-based regimens but remains rather infrequent. When treating melanoma with ICB, vitiligo-like depigmentation (VLD) is a relatively frequent adverse event that is associated with improved response [ 15 ]. However, this skin AE is not only mostly restricted to melanoma patients but also thought to be the equivalent of an on-target effect.…”

Vitiligo-like Lesions as a Predictor of Response to Immunotherapy in Non-Small Cell Lung Cancer: Comprehensive Review and Case Series from a University Center

“…They are typically characterized by a bilateral and symmetrical distribution pattern, with mostly smaller "freckle-like" macules, with a preferential distribution in ultraviolet-exposed areas (such as the face, hair, and hands), and with a median onset time of approximately 5 months. Melanoma patients with previous targeted therapy (with BRAF and MEK inhibitors) experience a significantly longer time lapse between ICI initiation and VLL onset compared to non-pretreated patients (12.5 vs. 6.2 months) [34,35]. Cytotoxic Tlymphocyte antigen-4 (CTLA4) inhibitor-induced VLLs were less frequent than they were with anti-PD-(L)1 treatment [19], although the combination of anti-PD-(L)1 and anti-CTLA4 usually results in a higher incidence of VLLs [9,19,36].…”

Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers

“…VLD is strongly associated with improved overall survival and progression-free survival, independent of other prognostic factors [ 14 ]. Hermann et al, 2022 observed that the upregulation of EDAR and downregulation of LAG3 was seen in responders amongst melanoma patients with VLD [ 15 ].…”