Case and Research Letters
Toxic epidermal necrolysis induced by vemurafenib
Necrólisis epidérmica tóxica por vemurafenib
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Lapresta, A. Dotor, C. González-Herrada" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Lapresta" "email" => array:1 [ 0 => "amlapresta@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A." "apellidos" => "Dotor" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "C." "apellidos" => "González-Herrada" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitario de Getafe, Getafe, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Universitario de Getafe, Getafe, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Necrólisis epidérmica tóxica por vemurafenib" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1627 "Ancho" => 1221 "Tamanyo" => 697919 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Histology showed extensive, confluent necrosis in the epidermis and subepidermal detachment. In the upper dermis, there was a predominantly perivascular lymphoplasmacytic infiltrate (hematoxylin-eosin, original magnification ×2.5).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We report the case of a 68-year-old man diagnosed with a nodular melanoma (Breslow depth, 11<span class="elsevierStyleHsp" style=""></span>mm) in the right submammary region. He had no relevant past history and reported taking no medication, Radiography showed enlarged bilateral axillary, mediastinal, and hilar lymph nodes and multiple bilateral micronodules in the upper and lower lobes of the lung. These nodules showed high uptake, suggestive of metastatic lesions, on the positron emission tomography–computed tomography scan. Assessment of the <span class="elsevierStyleItalic">BRAF</span> V600E mutation was positive. With a diagnosis of BRAF-positive stage IV metastatic melanoma, treatment was initiated with vemurafenib 960 mg every 12<span class="elsevierStyleHsp" style=""></span>hours. No reduction was observed in the metastases after almost a month of treatment.</p><p id="par0010" class="elsevierStylePara elsevierViewall">At week 4 of treatment, the patient presented at the emergency department of his reference hospital with itching and reddening of the face and scalp. He reported no previous symptoms or fever. The physical examination revealed an exanthematous macular-papular rash on the neck, trunk, and extremities. The patient was admitted and treated with oral corticosteroids and antibiotics. Over the next 48<span class="elsevierStyleHsp" style=""></span>hours, he developed dysphagia, a tendency towards low blood pressure, and decreased urine output. A severe drug reaction was suspected and the patient was transferred to the burn unit at our hospital. On arrival, 72<span class="elsevierStyleHsp" style=""></span>hours after the onset of symptoms, he was afebrile, hemodynamically stable, and breathing spontaneously. Physical examination showed extensive body surface involvement (85%) and epidermal detachment (60%), in addition to erosions affecting the ocular, oral, and genital mucosa (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>). His heart rate was 95<span class="elsevierStyleHsp" style=""></span>bpm and oxygen saturation was 100%.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Radiologic evaluation on admission showed enlarged hila and hilar and parahilar lymph nodes. There were no areas of consolidation. The most relevant laboratory findings were a C-reactive protein level of 86, a prothrombin ratio of 60.5%, and an internationalized normal ratio of 1.25. Biopsy showed extensive confluent necrosis in the epidermis and subepidermal detachment. There was a predominantly perivascular lymphoplasmacytic infiltrate in the dermis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). The patient was diagnosed with toxic epidermal necrolysis due to vemurafenib, with a score of 3 on the SCORTEN scale. Vemurafenib had been withdrawn on admission, and treatment initiated with intravenous ciclosporin 75<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>hours, in addition to selective digestive decontamination, vitamin and nutritional support, and fluid therapy. The necrotic areas of the skin were removed, cleaned with saline solution and chlorhexidine, and covered with Biobrane dressings (Smith & Nephew).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">During the first 48<span class="elsevierStyleHsp" style=""></span>hours of admission at our hospital, the lesions progressed to affect 90% of the total body surface. On day 4, the necrolysis stopped and the first signs of reepithelialization were seen. Reepithelialization was complete 2 weeks later.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Immediate complications were femoral deep vein thrombosis, followed by pulmonary embolism. Delayed complications included nail loss and adhesions in both external ear canals and in the balanopreputial sulcus. Finally, the patient required amniotic membrane transplantation due to necrosis of the conjunctival membranes.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The patient was discharged a month later. Ciclosporin was progressively tapered to zero, with administration of 150<span class="elsevierStyleHsp" style=""></span>mg and 100<span class="elsevierStyleHsp" style=""></span>mg for 5 days each. The patient returned to his reference hospital, where treatment with ipilimumab and radiation therapy reduced the metastases. He is currently stable and in good general health.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Vemurafenib is a selective inhibitor of the <span class="elsevierStyleItalic">BRAF</span> V600 mutation that was approved by the US Food and Drug Agency for the treatment of metastatic or unresectable melanoma in 2011.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> About 40% to 60% of melanomas are BRAF-positive, and the mutation causes constitutive activation of the mitogen-activated protein kinase pathway, which in turn leads to uncontrolled cell growth and increased cell proliferation and invasive capacity.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Most mutations are V600E (valine to glutamic acid substitution), but there are also other less common mutations, such as V600K.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the BRIM3 phase 3 clinical trial, 675 patients were randomly allocated to treatment with either vemurafenib or dacarbazine. In the vemurafenib group, there was a 63% reduction in the risk of death and a 74% reduction in the risk of death or disease progression.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> In addition, the phase 1 and 2 trials showed response rates of up to 50% and an overall mean survival of between 14 and 16 months.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">5,6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Treatment with vemurafenib, however, is not free of adverse effects, among which cutaneous toxicity is the most common. The most common cutaneous effects are rash, photosensitivity, pruritus, alopecia, palmar erythrodysesthesia, verrucal keratosis, keratoacanthomas, and squamous cell carcinomas. Almost 40% of patients develop a rash, which generally does not require treatment to be discontinued as most cases are mild (grade 1) or moderate (grade 2). Dose reductions or treatment discontinuation are only necessary in patients with severe rash (grade 3) or intolerable grade 2 rash.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Severe cutaneous reactions to vemurafenib are very uncommon, and just 1 case of Steven-Johnson syndrome and another of toxic epidermal necrolysis were reported in the BRIM3 study.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">However, new cases of severe cutaneous toxicity have appeared since the launch of the drug. Wantz et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> reported one of the first cases of toxic epidermal necrolysis due to vemurafenib in Europe. Treatment was discontinued and the necrolysis resolved, but the patient died from melanoma some months later.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The suspected drug should be withdrawn in all cases of toxic epidermal necrolysis and patients should be managed by specialized units. Although is no scientific evidence supporting the use of systemic therapy, at our hospital we use ciclosporin, as it rapidly stops progression of the rash, is well tolerated, and does not increase the risk of infection or death.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">We have presented the first case of toxic epidermal necrolysis due to vemurafenib in Spain. We believe that patients on this drug should be closely monitored by a dermatologist, with careful attention paid to the development of skin rash with signs of severity, such as epidermal detachment or mucosal involvement.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Lapresta A, Dotor A, González-Herrada C. Necrólisis epidérmica tóxica por vemurafenib. Actas Dermosifiliogr. 2015;106:682–683.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1221 "Ancho" => 1628 "Tamanyo" => 354872 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Generalized eruption consisting of erythematous macules, with a tendency to coalesce, flaccid blisters, and areas with erosions covered with Biobrane dressings.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1221 "Ancho" => 1628 "Tamanyo" => 295783 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Higher-magnification image showing large superficial blisters and areas of necrosis.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1627 "Ancho" => 1221 "Tamanyo" => 697919 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Histology showed extensive, confluent necrosis in the epidermis and subepidermal detachment. In the upper dermis, there was a predominantly perivascular lymphoplasmacytic infiltrate (hematoxylin-eosin, original magnification ×2.5).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved survival with vemurafenib in melanoma with BRAF V600E mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.B. Chapman" 1 => "A. Hauschild" 2 => "C. Robert" 3 => "J.B. Haanen" 4 => "P. Ascierto" 5 => "J. Larkin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1103782" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 4 | 14 |
| 2024 October | 89 | 40 | 129 |
| 2024 September | 84 | 21 | 105 |
| 2024 August | 107 | 57 | 164 |
| 2024 July | 80 | 31 | 111 |
| 2024 June | 102 | 29 | 131 |
| 2024 May | 60 | 29 | 89 |
| 2024 April | 78 | 24 | 102 |
| 2024 March | 73 | 30 | 103 |
| 2024 February | 53 | 40 | 93 |
| 2024 January | 58 | 28 | 86 |
| 2023 December | 70 | 19 | 89 |
| 2023 November | 75 | 26 | 101 |
| 2023 October | 84 | 28 | 112 |
| 2023 September | 79 | 39 | 118 |
| 2023 August | 52 | 22 | 74 |
| 2023 July | 54 | 29 | 83 |
| 2023 June | 53 | 21 | 74 |
| 2023 May | 72 | 24 | 96 |
| 2023 April | 64 | 20 | 84 |
| 2023 March | 55 | 27 | 82 |
| 2023 February | 39 | 21 | 60 |
| 2023 January | 39 | 29 | 68 |
| 2022 December | 45 | 44 | 89 |
| 2022 November | 37 | 24 | 61 |
| 2022 October | 24 | 24 | 48 |
| 2022 September | 25 | 39 | 64 |
| 2022 August | 26 | 36 | 62 |
| 2022 July | 26 | 37 | 63 |
| 2022 June | 35 | 25 | 60 |
| 2022 May | 34 | 39 | 73 |
| 2022 April | 47 | 36 | 83 |
| 2022 March | 36 | 50 | 86 |
| 2022 February | 23 | 29 | 52 |
| 2022 January | 25 | 38 | 63 |
| 2021 December | 37 | 39 | 76 |
| 2021 November | 45 | 40 | 85 |
| 2021 October | 32 | 49 | 81 |
| 2021 September | 24 | 31 | 55 |
| 2021 August | 25 | 16 | 41 |
| 2021 July | 22 | 25 | 47 |
| 2021 June | 15 | 20 | 35 |
| 2021 May | 31 | 19 | 50 |
| 2021 April | 63 | 56 | 119 |
| 2021 March | 54 | 23 | 77 |
| 2021 February | 65 | 25 | 90 |
| 2021 January | 30 | 15 | 45 |
| 2020 December | 24 | 12 | 36 |
| 2020 November | 27 | 21 | 48 |
| 2020 October | 29 | 5 | 34 |
| 2020 September | 43 | 17 | 60 |
| 2020 August | 21 | 21 | 42 |
| 2020 July | 31 | 16 | 47 |
| 2020 June | 34 | 30 | 64 |
| 2020 May | 28 | 8 | 36 |
| 2020 April | 33 | 11 | 44 |
| 2020 March | 29 | 11 | 40 |
| 2020 February | 3 | 0 | 3 |
| 2020 January | 4 | 4 | 8 |
| 2019 December | 8 | 0 | 8 |
| 2019 November | 4 | 1 | 5 |
| 2019 September | 8 | 1 | 9 |
| 2019 August | 4 | 0 | 4 |
| 2019 July | 2 | 0 | 2 |
| 2019 June | 6 | 1 | 7 |
| 2019 May | 2 | 8 | 10 |
| 2019 April | 0 | 1 | 1 |
| 2019 March | 2 | 3 | 5 |
| 2019 January | 6 | 0 | 6 |
| 2018 December | 11 | 0 | 11 |
| 2018 November | 3 | 0 | 3 |
| 2018 October | 4 | 0 | 4 |
| 2018 September | 8 | 0 | 8 |
| 2018 March | 1 | 0 | 1 |
| 2018 February | 81 | 4 | 85 |
| 2018 January | 29 | 5 | 34 |
| 2017 December | 67 | 10 | 77 |
| 2017 November | 18 | 2 | 20 |
| 2017 October | 20 | 8 | 28 |
| 2017 September | 13 | 7 | 20 |
| 2017 August | 23 | 6 | 29 |
| 2017 July | 17 | 9 | 26 |
| 2017 June | 18 | 10 | 28 |
| 2017 May | 18 | 6 | 24 |
| 2017 April | 22 | 7 | 29 |
| 2017 March | 21 | 10 | 31 |
| 2017 February | 14 | 9 | 23 |
| 2017 January | 14 | 6 | 20 |
| 2016 December | 15 | 21 | 36 |
| 2016 November | 28 | 25 | 53 |
| 2016 October | 20 | 28 | 48 |
| 2016 August | 1 | 1 | 2 |
| 2016 July | 1 | 2 | 3 |
| 2016 June | 4 | 0 | 4 |
| 2016 May | 1 | 0 | 1 |
| 2016 April | 3 | 0 | 3 |
| 2016 February | 0 | 4 | 4 |
| 2015 November | 0 | 2 | 2 |
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