Stevens–Johnson syndrome-like cutaneous toxicity with enfortumab vedotin in treating metastatic urothelial carcinoma: A case report
Year: 2024
Type: article
Study design: Case Report
Abstract: Dear Editor, Enfortumab vedotin (EV) is an antibody–drug conjugate used to treat locally advanced and metastatic urothelial cancer.[1] It is an anti-nectin-4 monoclonal antibody combined with monomethyl auristatin E, disrupting microtubules to induce cancer cell death, particularly in urothelial cancers where nectin-4 is overexpressed. Enfortumab vedotin (EV) is for patients previously treated with PD-1/L1 inhibitors and platinum-containing chemotherapy or those ineligible for these treatments. Dermatologic events may arise with EV use due to nectin-4 expression in skin cells.[2] The recommended EV dose is 1.25 mg/kg (up to 125 mg), administered intravenously on days 1, 8, and 15 of a 28-day cycle. A 78-year-old male with diabetes and diabetic nephropathy underwent a kidney transplant 11 years ago. Three years ago, he was diagnosed with renal pelvic urothelial carcinoma after presenting with hematuria. Following surgery and chemotherapy, advanced lymph node metastasis in the local region was observed 8 months ago. Due to concerns about potential transplant rejection from PD-1/L1 inhibitors, treatment shifted to EV. He received EV at 1.25 mg/kg on Day 1 of the first cycle with no initial adverse effects. However, within 24 h of the Day 8 infusion, diffuse pruritus became evident. EV therapy continued alongside topical corticosteroids. On Day 15, skin rash and pain developed after the third dose of EV at 1.25 mg/kg. Due to the worsening rash, hospitalization was necessary by Day 19. No fever was observed throughout the course, and cardiovascular, respiratory, and laboratory examinations were stable and unremarkable. Dermatological examination revealed diffuse tender dusky erythema on the trunk and ruptured bullae in the axillae, lower abdomen, scrotum, and inguinal folds [Figure 1a-c]. The oral mucosa and conjunctiva were unaffected. Erythema affected 40% of the body surface area, with skin detachment in about 6% of affected areas. The Nikolsky sign was positive. Serological analysis for anti-intercellular substance and anti-basement membrane zone antibodies was negative. An incisional biopsy of the right axilla confirmed a subepidermal blister with detached epidermis [Figure 1d], accompanied by limited perivascular lymphocytes and eosinophil infiltration [Supplementary Figure 1a-d]. There were only a few dyskeratotic cells, but many keratinocytes exhibiting starburst mitotic features, suggestive of cell cycle arrest.[3] Similar histopathological findings were noted in skin appendages such as sweat glands and hair follicles. Direct immunofluorescence yielded negative results [Supplementary Figure 1e and f]. Using the algorithm of drug causality for epidermal necrolysis,[4] which was originally used to assess Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis, EV was scored 3 indicating a possible causality.Figure 1: Clinical manifestation. (a-c) Three days after the third dose of EV, dusky erythema on the trunk, flaccid ruptured bullae, and skin detachment were noted in the axillae, scrotum, and inguinal folds. (d) Skin biopsy site on the right axillary area. (e and f) 17 days after the third dose of EV, the skin has re-epithelialized and started peeling off, darkening in the process.Supplementary Figure 1: Pathology. (a) Histopathologic analysis revealed subepidermal blister with detached epidermis along with a sparse infiltration of perivascular lymphocytes and eosinophils. (b) A small number of dyskeratotic cells were observed. Notably, keratinocytes displaying starburst mitotic characteristics (red arrow) were identified, suggesting arrest in the cell cycle. (c and d) Starburst mitotic features (red arrow) were also detected in skin appendages such as sweat glands and hair follicles. (e and f) The results of direct immunofluorescence staining for IgG and C3, respectively.Rapid rash-onset post-EV initiation led to drug discontinuation due to suspected causation. Grade 3 severe cutaneous adverse events were diagnosed, with suspicion of “EV-related skin toxicity” or SJS. We initiated systemic corticosteroid therapy with methylprednisolone at 0.5 mg/kg per day, alongside topical clobetasol cream for the rash. To prevent infection, we treated with antibiotics, used nonadherent dressings, ensured hydration, and provided zinc supplements and nutrition. The patient improved and was discharged after 12 days [Figure 1e and f]. Based on the clinical pathological findings, response to treatment, and many prior case reports, we believe that EV may induce a distinctive cutaneous adverse reaction, characterized by the peculiar appearance of painful erythema, blistering, and desquamation occurring primarily within major skin folds.[5,6] Most EV-related skin adverse reactions are typically observed during the first treatment cycle (average of 0.6 months).[7] The absence of initial adverse reactions in this patient is likely due to the cumulative nature of skin toxicity resulting from keratinocyte cell cycle arrest. Unlike typical SJS, these desquamative adverse reactions typically involve minimal or no mucosal damage, lack characteristic targetoid red spots, and respond rapidly to therapy. Pathologically, scattered ring and starburst mitoses and dyskeratosis were observed in the epithelium, sweat glands, and hair follicles, along with perivascular lymphocytic and eosinophilic infiltration. In contrast, SJS is characterized by full-thickness epidermal necrosis. Both reactions may exhibit interface dermatitis, making differentiation challenging. Thus, the primary pathological distinction lies in the varied mechanisms of keratinocyte damage and necrosis.[1] We infer that this reaction may stem from direct cellular toxicity of the medication, distinct from immune-mediated SJS,[5] and both clinically and in treatment response. “EV-related skin toxicity” would be a more fitting term. In addition, we speculate most previous case reports fall into this category. According to EV drug labels and clinical trials, most cases of this cutaneous toxicity can be managed by dose reduction of EV and systemic steroids treatment, highlighting its dose-dependent nature and mechanistic differences from SJS.[8] Therefore, early confirmation of EV-related skin toxicity is crucial for dermatologists and urologists, as it significantly influences subsequent treatment decisions for advanced urothelial cancer. Declaration of patient consent The authors affirm that they have obtained requisite patient consent documentation. Said documentation includes the patient’s explicit authorization for the publication of their images and pertinent clinical data within the journal. The patient is cognizant that their identity, specifically their name and initials, will be withheld from publication, and diligent efforts will be undertaken to preserve anonymity. However, it is acknowledged that absolute anonymity cannot be unequivocally 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 There are no conflicts of interest.
Source: Dermatologica Sinica
Authors: Yun-Chang Li, Sung-Lang Chen, Tung-Ying Ke, Tsu-Man Chiu
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $70
OpenAlex ID: W4403307110