Extensive bullous lichenoid drug eruption associated with the combination therapy of enfortumab vedotin and pembrolizumab: A case report
Year: 2024
Type: article
Study design: Case Report
Abstract: Dear Editor, Enfortumab vedotin (EV) is a humanized antibody-drug conjugate approved in 2019 as a third-line treatment for locally advanced or metastatic urothelial carcinoma. Despite significantly prolonged survival, skin reactions were reported in 47% of patients receiving EV.[1] To enhance antitumor activity, clinical trials combining EV with pembrolizumab have been conducted.[2] Here, we report a case of extensive bullous lichenoid skin eruption after receiving a combination therapy of EV and pembrolizumab for the treatment of urothelial carcinoma. A 70-year-old woman with high-grade metastatic urothelial carcinoma was referred to the dermatology department for progressive skin eruptions. She had been enrolled in a clinical trial and received the combination therapy of pembrolizumab and EV on day 1 and EV only on day 8 of a 21-day cycle. One week after receiving the first cycle, she developed diffuse, pruritic, erythematous, maculopapular rashes with superficial desquamation on the trunk, and four limbs involving 40% of the total body surface area (TBSA), consistent with a Grade 2 skin reaction according to the Common Terminology Criteria for Adverse Events. During the following three cycles, she developed similar episodes of skin rash 3–5 days postinfusion. These episodes were managed through the administration of topical and systemic oral steroids, alongside dose reductions and temporary cessations of the combination therapy. Follow-up pelvic computed tomography revealed regression in the patient’s urothelial carcinoma, demonstrating a positive response to the combination therapy. However, 2 weeks after the fifth cycle of EV/pembrolizumab combination therapy (approximately 4 months after the initiation of the first cycle), the patient developed generalized pruritic and scaly skin rashes affecting >70% of TBSA, with further blisters formation. Physical examination revealed generalized erythematous papules that coalesced into well-demarcated lichenoid plaques, with vesicle and bullae formation at the margins of the lesions, giving an annular appearance [Figure 1]. The lesions were mainly located on the extensor surface of the trunk and limbs, with the flexor sides relatively spared. The mucous membranes were not affected. Laboratory examination revealed peripheral eosinophilia and an elevated immunoglobulin (Ig) E level (6763.0 IU/mL).Figure 1: Extensive involvement of body surface with relative sparing of flexor sites (a). Coalescing lichenoid plaques with desquamation with prominent vesicles and bullae formation at the expanding borders of the lesions (b and c). Vesicles formation giving an annular appearance (d).Histopathology showed intraepidermal and subepidermal vesicles, numerous dyskeratotic keratinocytes, a lichenoid lymphocytic infiltrate with prominent eosinophils, and focal interface vacuolar changes with pigment incontinence [Supplementary Figure 1]. Direct immunofluorescence examination of the perilesional skin showed that subepidermal vesicles were located above the type IV collagen. No deposition of IgG, IgA, IgM, C3, or fibrinogen was detected [Supplementary Figure 2]. A diagnosis of bullous lichenoid drug eruption was made, and the patient was treated with intravenous prednisolone at a dose of 1 mg/kg/day. Following 5 days of treatment, there was a reported decrease in pruritus and blister formation. The systemic steroid was then gradually tapered, with a 20% dose reduction every 3–4 days, and the lesions gradually abated with postinflammatory hyperpigmentation. Owing to the severe skin adverse reaction, pembrolizumab was discontinued starting from cycle 6, and the patient was shifted to monotherapy with EV. Over 2 years of follow-up, the patient’s disease remained stable without any progression. However, Grade 1–2 skin reactions, predominantly maculopapular rashes or erythematous patches with desquamation, were still observed following each cycle of EV therapy.Supplementary Figure 1: Histological examination showed intraepidermal and subepidermal blisters with marked dyskeratosis (a). There was also focal parakeratosis and hypergranulosis, dyskeratosis, lichenoid lymphocytic and eosinophilic infiltrate in the superficial dermis (b).Supplementary Figure 2: Direct immunofluorescence examination shows subepidermal vesicles (arrows) located above the type IV collagen (a). No deposition of immunoglobulin (Ig) G, IgA, IgM, C3, or fibrinogen was detected (b-f).EV is consisted of an antinectin-4 antibody and a microtubule disruptor, monomethyl auristatin E, which can selectively lead to apoptotic cell death of nectin-4-expressing cells. Although nectin-4 is highly expressed in cancer cells, it was also weakly to moderately expressed in human skin keratinocytes, sweat glands, and hair follicles.[3] This may explain the frequent occurrence of EV-related skin toxicity. The EV-related rash occurs on average within the first cycle and is usually described as a “maculopapular” rash with occasional vesicle/bullae formation.[4] Histopathologic findings include vacuolar interface dermatitis, epidermal spongiosis, atypical mitosis, and marked dyskeratosis.[5] Most immunofluorescence studies showed negative results, but in a recent report, cell surface deposits of IgG and C3 were detected in the upper epidermis in two cases, which correlated with the site of nectin-4 expression.[6] Lichenoid eruptions are a known cutaneous adverse reaction of immune checkpoint inhibitors, occurring in 0.5% to 6% of patients and taking an average of 6–12 weeks to appear.[7] Clinically, it resembles lichen planus but shows a relatively symmetrical distribution with a predilection for the trunk and the extensor surface of the extremities. Bullous lichenoid drug eruption, such as bullous lichen planus, may result from excessive edema associated with basement membrane zone damage, indicating hyperactivity of the inflammatory process. Cases of bullous lichenoid drug eruptions associated with immune checkpoint inhibitors have been rarely described, and none of them showed such extensive disease as our case. Although the mechanism of a lichenoid drug eruption is not fully understood, cytotoxic T cells are thought to play a crucial role in inducing apoptosis of basal epidermal keratinocytes.[8] EV-induced cell death may trigger the presentation of keratinocyte autoantigens from antigen-presenting cells to autoreactive T cells, which may enhance further hypersensitivity reactions. Skin affected by EV toxicity may, therefore, be more susceptible to immune-related cutaneous adverse events and present clinically with greater TBSA involvement and bullae formation. In summary, our case demonstrated extensive bullous lichenoid dermatitis with prominent annular vesicle formation 4 months after the initiation of EV/pembrolizumab combination therapy. Further studies are needed to better understand the mechanism of EV-related skin toxicity and its possible interaction with immune checkpoint inhibitors. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent form. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Data availability statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest Dr. Chih-Chiang Chen, an Associate Editor at Dermatologica Sinica, had no role in the peer review process or the decision to publish this article. Dr. Li-Hsin Wang declared no conflicts of interest with regard to this study and paper.
Source: Dermatologica Sinica
Authors: Li-Hsin Wang, Chih-Chiang Chen
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $70
OpenAlex ID: W4404792767