Enfortumab vedotin

Abstract

Stevens-Johnson syndrome/toxic epidermal necrolysis and dermal hypersensitivity reaction: 2 case reports A case report described two men aged 71–77 years; they developed Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/ TEN) and dermal hypersensitivity reaction (1 patient each) during treatment with enfortumab vedotin for metastatic urothelial carcinoma. Patient 1: A 71-year-old man, who had been receiving various medications for multiple morbidities including metastatic urothelial carcinoma, for which he had been treated with multiple lines of chemotherapy, subsequently started receiving enfortumab vedotin infusions 1.25 mg/kg on days 1 and 8 of cycle 1. However, within 24 hours of receiving the infusion on day 8, he developed diffuse pruritus. Four days later, he presented to hospital with mouth pain and fever up to 101°F. Dermatologic examination revealed a small ulceration on his right lateral upper lip, as well as a well-demarcated erythema of the inferior tongue tip, in addition to tender erythema of his axillae, flanks, soles of the feet and inguinal region. He was found to have flaccid ruptured bullae with involvement of about 11% of his body surface area, including his right heel, his right posterior upper arm and his left forearm, with a positive Nikolsky sign. He was admitted and treated with unspecified systemic steroids. Four days following the onset of his symptoms, punch biopsy of his left axillae confirmed subepidermal bulla with detached epidermis and scattered dyskeratotic cells with mixed dermal inflammatory infiltrate, consisting of lymphocytes, eosinophils, neutrophils and macrophages. The clinical and histologic findings were consistent with early changes of SJS/TEN. The inflammatory infiltrate consisted of CD4+ and CD8+ T-cells admixed with MPO+ neutrophils and scattered CD68+ macrophages. Immune profiling revealed that the density of skin infiltrating lymphocytes was predominantly composed of CD4+ T-cells with a subset of CD8+ T-cells. The Th immune profile primarily consisted of Th2 (Gata3+ cells) and Tregs (FoxP3+ cells) lymphocytes. The Th17 (RORgT+ cells) were a subset of CD4+ T-cells, and a minor population was Th1 (anti-TBet+ cells). Hence, he was transferred to the ICU, where he received IV methylprednisolone on day 3 for involvement of 18% of his total body surface area, and a high SCORETEN of 7. He also received antimicrobial therapy with aciclovir, cefepime and mupirocin. However, in spite of receiving methylprednisolone, the rash worsened, indicating lack of efficacy. He further developed hypotension, acute kidney injury, hyponatraemia, hyperglycaemia, anion gap metabolic acidosis and atrial fibrillation with rapid ventricular rate. Full thickness ulcers developed on his left upper arm, bilateral axillae, right forearm, posterior ankles and scrotum with positive Nikolsky sign. He was subsequently transferred to the burn unit of a nearby hospital; however, he passed away due to SJS/TEN several days later. Patient 2: A 77-year-old man, who had previously been treated for metastatic urothelial carcinoma, subsequently started receiving enfortumab vedotin infusions [dosage not stated]. However, 2 days after the third infusion, he developed a rash, with tender erythema in his axillae, inguinal folds and scrotum. He was also found to have pruritic papules and vesicles of his chest and back, as well as bullae on the dorsal second and third digits of his left foot. Eighteen days post his first infusion, skin biopsy of his chest revealed bullous formation, while skin biopsy of an inguinal fold showed interface dermatitis with dyskeratosis, with associated eosinophils and some neutrophils. These clinical and pathologic findings were consistent with enfortumab vedotin-associated drug toxicity. Immunohistochemical studies showed perivascular dermal infiltrates with CD4+ and CD8+ T-cells, as well as scattered CD68+ macrophages with few MPO+ neutrophils in the blister cavity. Immunofluorescence studies demonstrated primarily CD4+ T-cell lymphocyte density with Tregs (FoxP3+ cells) in both lesions. The interface dermatitis toxicity in the inguinal fold biopsy showed a higher density of CD8+ lymphocytes as compared to the bullous toxicity in the chest biopsy; also, there was a higher density Th17 (RORgT+ cells) in former, as compared to the latter. The Th1 subset (TBet+ cells) of lymphocytes consisted of a small population of skin infiltrating lymphocytes with higher density of Th1 subset in the interface dermatitis toxicity (lesion 1), as compared to bullous toxicity (lesion 2). The density of Th2 lymphocytes (Gata3+ cells) was greater in lesion 2, as compared to the lesion 1. His ALT and AST levels were elevated to 89 U/L and 99 U/L, respectively. He was treated with silver sulfadiazine cream, triamcinolone ointment and prednisone, resulting in significant improvement in his rash and liver enzyme levels after 24–48 hours of treatment. He continued receiving enfortumab vedotin without further complications.