In this single institution series of ICI-induced vitiligo, we reviewed 151 consecutive patients with melanoma and non-melanoma cancers. In our cohort, all Food and Drug Administration (FDA)-approved ICIs have the capacity to induce vitiligo. ICIs are most frequently used in melanoma therapy and ICI-induced vitiligo is most strongly associated with melanoma [2]. As expected, our cohort had mostly melanoma patients (132, 87.4%), with the most prevalent race overall being Caucasians (108, 71.5%). Our cohort of 19 (12.6%) non-melanoma patients, however, definitively challenges the previously held notion that ICI-induced vitiligo is limited to melanoma patients. Specifically, ICI-induced vitiligo in patients with angiosarcoma, Hodgkin’s lymphoma, and mycosis fungoides were not previously reported in the literature. Thus, it appears that ICI-induced vitiligo can be caused by a much wider range of cancers than previously expected, and the mechanism of ICI-induced vitiligo deserves further exploration.
We noted that non-melanoma patients had a statistically significant difference (p = 0.005) in median time to onset of vitiligo compared to melanoma patients with 382 days versus 209 days, respectively. As ICI-induced CAEs generally occur on average within 4 weeks after ICI initiation [1], it is interesting to note the delayed onset. It is, however, unclear if ICI-induced vitiligo truly has a delayed onset like ICI-induced bullous pemphigoid, or if vitiligo has a delayed diagnosis. The low acuity and asymptomatic nature of vitiligo increase the risk of delayed diagnosis and under reporting. It is especially prone to delays in diagnosis in lighter skin types where vitiligo is more difficult to detect and there is a lower cosmetic impact. Of note, the majority of the patients in our cohort were Caucasian (71.5%). In combination, these factors likely result in an erroneously low number of reported patients with vitiligo secondary to ICI. Further, patients with non-melanoma cancers’ longer time to onset may be explained by these patients not receiving regular full-body skin exams from a dermatologist as their melanoma counterparts do. Definitive incidence and time to onset data would require more standardized skin exams and ideally, prospective reporting.
Vitiligo outcomes in our cohort showed 117 patients (78%) had stable disease, while 26 (17.3%) worsened and 7 (4.7%) improved. This supports vitiligo as a predominantly non-progressive disease. The majority (91.4%) of our patients were not treated for their vitiligo and were offered reassurance with sun protection alone. As many patients also opted not to treat the vitiligo, it is difficult to discern precisely whether no treatment was desired or no treatment was offered. This is not unexpected as vitiligo is predominantly an asymptomatic disease in fair-skinned patients, and thus low priority in the setting of metastatic melanoma. With the expanding use of checkpoint inhibitors for non-melanoma cancers, however, the diversity of patients’ skin color is also expected to increase, leading to a greater impact of vitiligo on quality of life and greater importance of vitiligo outcomes. Of note, two African American patients were treated with narrowband ultraviolet B (NB-UVB). Both experienced vitiligo improvement, with one patient experiencing dramatic re-pigmentation. In a previous report, a Hispanic male with renal cell carcinoma experienced improvement of his ICI-induced vitiligo after being treated with NB-UVB in combination with topical steroids, after lack of improvement on topical steroids alone [12]. This points to the effectiveness of the current gold standard treatment of topical steroids and UV light therapy for vitiligo in the ICI-induced variant. In addition, one patient in our cohort was depigmented with topical hydroquinone. It is important for clinicians to keep in mind that for some patients with severe vitiligo, depigmentation therapy can prove a better cosmetic alternative, if the patient is amenable, than repigmentation. Overall, it is reasonable to not treat patients, especially if the vitiligo is asymptomatic and patients are not impacted cosmetically. As studies in skin-of-color (SOC) patients have shown that vitiligo can have a variety of negative impacts on mental health [13], treating vitiligo with NB-UVB alone or in combination with topical steroids can prove fruitful in this setting. As ICIs are increasingly utilized in non-melanoma cancers where there is greater diversity of patients, physicians should be aware of potential quality of life impacts of ICI-induced vitiligo and potential effective treatment options.
It has been hypothesized that vitiligo secondary to ICI therapy in melanoma patients is associated with increased tumor response as it indicates the therapy is effectively targeting melanocytes. This is reflected through the association of ICI-induced vitiligo with increased progression-free survival, overall survival, and complete or partial response to treatment in melanoma patients [9–11]. The ICIs supposedly induce a tumor response against antigens that are present on both benign and malignant melanocytes resulting in vitiligo [10, 11]. This theory, however, bears further exploration in light of the variety of non-melanoma cancers similarly associated with ICI-induced vitiligo. The heterogeneity and small size of our cohort does not allow for this analysis.
Time to next treatment (TTNT) is defined as the time between start date of vitiligo-inducing ICI and the start date of next systemic treatment. This metric represents the clinical benefit of therapy by accounting for both tumor response as well as toxicity profile in disease or treatments which are highly symptomatic. In our cohort, TTNT was similar in melanoma and non-melanoma patients, with a median TTNT of 797 and 983 days respectively. This raises the question of whether ICI-induced vitiligo could be associated with increased clinical benefit in non-melanoma patients and would be worth further prospective analysis.
In comparing our cohort of melanoma patients with vitiligo to that of previously studied consecutively treated standard of care melanoma patients from our institution, we noticed a trend toward higher median TTNT in the vitiligo patients (Table 4). Because of the disparity in sample sizes, meaningful time-dependent analysis was not possible with our data. Of note, in our sub-group of melanoma patients treated with combination ICI therapy, the median TTNT was almost three times longer than in previous studies with 623 and 210 days respectively (Table 4).
Table 4
Time to Next Treatment Comparison of Melanoma Treatment Arms to Prior Studies
|
Melanoma Combination Therapy
|
|
|
Prior Study (n=155)
|
Our Cohort (n=53)
|
Median TTNT (days)
|
210
|
623
|
Range TTNT
|
21-1273
|
42-2089
|
|
Melanoma Nivolumab Therapy
|
|
|
Prior Study (n=63)
|
Our Cohort (n=39)
|
Median TTNT (days)
|
289
|
784
|
Range TTNT
|
20-1523
|
91-1878
|
|
Melanoma Pembrolizumab Therapy
|
|
|
Prior Study (n=215)
|
Our Cohort (n=31)
|
Median TTNT (days)
|
429
|
1386
|
Range TTNT
|
13-2108
|
14-2854
|
|
Melanoma Total
|
|
|
-
|
Our Cohort (n=132)
|
Median TTNT (days)
|
-
|
797
|
Range TTNT
|
-
|
14-4873
|
|
Non-Melanoma
|
|
|
-
|
Our Cohort (n=19)
|
Median TTNT (days)
|
-
|
983
|
Range TTNT
|
-
|
120-1895
|
TTNT = Time to next treatment |
Based on our data alone, overall 5-year survival within the melanoma group was highest with pembrolizumab therapy, followed by nivolumab and ipilimumab-plus-nivolumab therapy. As our cohort includes mainly standard of care patients, it is likely that ipilimumab-nivolumab combination therapy was used to treat those with aggressive disease and monotherapy may have been used more for adjuvant therapy, accounting for the lower overall survival in the combination treatment arm. Our cohort’s 1, 2, and 5-year overall survival rates were found to be higher than previously reported clinical trials among all treatment arms (Table 3) [14–18]. Overall 5-year survival has been previously reported at 34% with pembrolizumab, 52% with ipilimumab-plus-nivolumab, and 44% with nivolumab therapies in clinical trials. OS within our cohort was at 87%, 56.8% and 79.7% for the same respective categories of therapy [15, 18].
Although direct comparison between real-world and clinical trials patients cannot be made, the increased OS rates and TTNT in our study may represent associated clinical benefit in the setting of ICI-induced vitiligo. Further study into the mechanism may aid in our understanding of the effect of ICI-associated vitiligo on TTNT and overall survival outcomes in melanoma patients. At this time, we are only discussing an association, which may have confounders such as patients having good enough response and low enough toxicity profile to remain on ICI therapy long enough to develop vitiligo. Mechanistic causation has yet to be established.
One limitation we noted in our chart review is that reporting of vitiligo was often inconsistent with skipped notes in documentation and non-specific descriptions of the disease. In combination with the single cohort nature of this study, this inconsistency complicates the calculation of incidence numbers as well as time to onset due to potential delays in reporting. With time to onset being dependent on patient or physician observation of vitiligo, a lower number of cases may also have been reported. The distribution of the patients’ disease may also affect the likelihood of diagnosis or documentation. This is supported in our cohort by vitiligo distribution, 95 (62.9%) patients had face/neck involvement and 104 (68.9%) had upper extremities involvement, areas that are easily noticed by the patient and clinicians. In contrast, only 53 (35.1%) had trunk and 51 (33.8%) had lower extremities involvement. Incidence was not calculated in this study due to the above recognized limitations.
Another limitation is that of the 151 patients reviewed, 39 had ICI treatments prior to the ICI they were on when vitiligo was noted in their electronic medical record. This represents a confounding variable in the treatment that definitively caused the vitiligo. Since time to onset can be delayed, it is possible that the prior ICI is the treatment that caused the vitiligo rather than the ICI the patient was currently being treated with when the vitiligo started. Though the exact vitiligo-inducing ICI may be unknown in these patients, it remains reasonable to assume that they had ICI induced vitiligo and should remain as part of the cohort.
In conclusion, ICI-induced vitiligo can be seen with virtually any cancer type and there are multiple reasons for delayed and under reporting. As the cancer types treated with ICIs expands, it is important for patient care teams to recognize the quality-of-life impact on an increasingly diverse patient population and to treat their skin disease accordingly.