Vemurafenib‐induced toxic epidermal necrolysis: possible cross‐reactivity with other sulfonamide compounds

Vemurafenib is a newly licensed target‐directed medication. It has been proven to improve the survival of patients with metastatic melanoma and the BRAF^V600E mutation; however, adverse cutaneous reactions are frequent. Few cases of life‐threatening severe cutaneous adverse reactions (SCARs) induced by vemurafenib have been reported. Dabrafenib, another selective BRAF inhibitor, has been licensed recently as an alternative drug with the same indications. From a molecular point of view, both vemurafenib and dabrafenib contain a sulfonamide group; cross‐reactivity to sulfonamide compounds has been reported in allergic patients. We report on a patient with vemurafenib‐induced toxic epidermal necrolysis (TEN). In vitro analysis of lymphocyte reactivity to vemurafenib showed positive results, confirming drug causality. In addition, lymphocytes from the patient reacted to dabrafenib and to the antibiotic sulfonamide drug sulfamethoxazole. Moreover, lymphocytes from two patients with cutaneous adverse reactions to sulfamethoxazole also reacted to vemurafenib and dabrafenib in vitro. These data strongly suggest that there might be clinical cross‐reactivity between BRAF inhibitors and sulfonamides in some patients. Thus, precautions should be taken to avoid sulfonamide drugs as much as possible in patients showing serious hypersensitivity reactions to vemurafenib and vice versa.     

Unexpected recalcitrant course of drug‐induced erythema multiforme‐like eruption and interstitial pneumonia sequentially occurring after nivolumab therapy

Vemurafenib improves survival of melanoma patients. However, cutaneous side‐effects commonly occur in them. Nivolumab and ipilimumab are monoclonal antibodies against programmed death 1 and cytotoxic T‐lymphocyte‐associated antigen 4, both of which regulate excessive T‐cell activation. Although these agents induce antitumor immunity against melanoma, the modified immune condition may result in an unexpected adverse reaction which has not been observed previously. Herein, we report a case who manifested severe erythema multiforme‐like eruption with mucosal involvement associated with vemurafenib following nivolumab. The patient also subsequently suffered from ipilimumab‐induced interstitial pneumonia with refractory course. Such a case has never been reported. This case suggested that dermatologists should pay special attention to unexpected adverse events of these drugs, and carefully observe cutaneous and respiratory status of patients during the treatment of melanoma.     

Vemurafenib: an unusual UVA‐induced photosensitivity

Vemurafenib is a new‐targeted therapy approved for the treatment of patients with V600E BRAF‐mutant metastatic melanoma. Among the cutaneous adverse events reported, the photosensitivity is frequently experienced. We aimed to characterize more deeply the mechanism leading to this photosensitivity as well as the corresponding UV spectrum. Phototests showed that the phototoxicity was UVA‐dependent since from normal value prior to vemurafenib treatment, the UVA‐minimal erythema dose decreased in 17 of 18 patients (94.4%) while the minimal erythema dose remained unchanged. Furthermore, a vemurafenib‐induced erythema appeared quickly during the UVA exposure contrarily to what is observed with a conventional drug‐induced phototoxicity showing an erythema 12–24 h after the phototesting. Vitamin PP concentration decreased, and porphyrin level significantly increased after 2 months of vemurafenib. Our study confirms the high risk of vemurafenib‐induced photosensitivity and indicates that it is possibly vitamin PP‐ and porphyrin dependent.     

Vemurafenib‐induced hyperkeratosis of the areola treated with topical adapelene

We present a rare condition, hyperkeratosis of the areola, induced by vemurafenib. Only a few papers have described an association of BRAF inhibitors with hyperkeratosis of the areola and/or nipple. Vemurafenib is a selective BRAF inhibitor used in patients with unresectable or metastatic melanoma who are positive for the V600 mutation. This drug has been associated with numerous cutaneous side effects, both benign and malignant. We report a male patient with vemurafenib‐induced hyperkeratosis of the areola managed successfully with a topical retinoid, and describe for the first time a treatment for this side effect.     

Aromatase inhibitor‐induced skin adverse reactions: exemestane‐related cutaneous vasculitis

Background Three aromatase inhibitors, namely anastrozole, letrozole and exemestane, which reduce circulating oestrogen, are used to treat breast cancer patients; the therapeutic use of such aromatase inhibitors is quickly increasing. Objective We intended (i) to review aromatase inhibitor‐induced cutaneous adverse effects and (ii) to describe a recently observed case of cutaneous vasculitis triggered by exemestane. Patients/methods The so‐far reported literature cases of aromatase inhibitor‐induced cutaneous adverse effects were analysed retrospectively. Especially, the clinical case of exemestane‐induced cutaneous vasculitis herein reported is unique, because such an observation has not yet been published in the literature. Results Merely 12 cases of cutaneous adverse reactions induced by aromatase inhibitors, namely erythema nodosum (6), subacute cutaneous lupus erythematosus (1), cutaneous rashes (2), vasculitis (3, including the one described in this study), are reported in the literature. In fact, in the present case, cutaneous vasculitis was strictly related to exemestane. Conclusion As aromatase inhibitors (e.g. exemestane) are increasingly incorporated into the treatment strategy of breast cancer patients, it is important to recognize possible cutaneous adverse effects. Specifically, with regard to cutaneous vasculitis, some patients might progress to severe vasculitis manifestations if the offending drug (e.g. exemestane) is not quickly stopped.     

Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis,prevention and management of the main treatment‐related skin toxicities

Until recently, no effective treatment was available for patients with metastatic malignant melanoma, and median overall survival was little more than 6 months with the current standard of care, dacarbazine. In 2012, the first specific BRAF mutation inhibitor, vemurafenib, was licensed for the monotherapy of adults with BRAF V600 mutation‐positive unresectable or metastatic melanoma. Like other targeted therapies, vemurafenib is associated with a predictable pattern of adverse events, including skin toxicities. We review the most common cutaneous adverse events associated with vemurafenib, based on data from clinical trials, and our own experiences of treating patients in trials and clinical practice. Overall, these toxicities are not preventable, but they rarely necessitate permanent treatment discontinuation and are generally manageable with dose modification and supportive care. We provide a treatment algorithm offering guidance on the most appropriate approach to managing the main skin toxicities to help clinicians unfamiliar with this novel agent to become confident in using vemurafenib effectively in the management of patients with metastatic melanoma.     

Vemurafenib‐Induced Neutrophilic Panniculitis in a Child with a Brainstem Glioma

Neutrophilic panniculitis is a rare adverse effect of therapy with selective BRAF inhibitors. We report a case of neutrophilic panniculitis in a 15‐year‐old girl receiving treatment with vemurafenib for a brainstem glioma. Clinicians should be aware of this rare but important side effect of vemurafenib. This is the first report of neutrophilic panniculitis in a child treated with vemurafenib.     

Vemurafenib and cobimetinib‐induced toxic epidermal necrolysis in a patient with metastatic melanoma

Combination therapy in the treatment of metastatic melanoma has been associated with more durable response rate compared to monotherapy. However, previous studies have shown that combined target therapy commonly causes a wide spectrum of adverse events. These adverse reactions are usually manageable, however, it is always necessary to compare drug efficacy with its potential adverse effects. Toxic epidermal necrolysis represents severe mucocutaneous reaction, usually triggered by medications and characterized by extensive necrosis and detachment of the epidermis. Here we present a first case of toxic epidermal necrolysis induced by combined target therapy (vemurafenib plus cobimetinib). The case was observed in a young patient with BRAF mutant melanoma who was started on first‐line metastatic immunotherapy with pembrolisumab.     

Efficacy and safety of dabrafenib–trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF‐V600 mutation: A systematic review and network meta‐analysis

The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib – trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF‐V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta‐analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF‐V600 mutation (NMA‐pBRAFV600) and another with mixed population (with or without the mutation: NMA‐pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA‐pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA‐pBRAFV600. Dabrafenib–trametinib was found to have a favorable effect on overall survival (OS) and progression‐free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA‐pMixed, dabrafenib–trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib–trametinib and vemurafenib–cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib–trametinib has a favorable effect on Grades 3 and 4 adverse events.     

Case of vemurafenib‐induced Sweet's syndrome

Vemurafenib is a targeted therapy that has become standard treatment for patients with advanced melanoma with a V600E BRAF mutation. It has been associated with frequent skin toxicity, including photosensitivity, rash and squamous cell carcinomas. We present an 83‐year‐old woman with an advanced V600E BRAF‐mutant melanoma who developed a severe skin rash and fatigue after taking vemurafenib. The dose was reduced from 960 to 720 to 480 mg twice a day; however, she was subsequently admitted to the hospital with fever, chills, fatigue, confusion and a diffuse skin eruption. She then developed hypoxia and acute renal failure that required hemodialysis. A biopsy of her skin lesions revealed a neutrophilic dermatitis with papillary dermal edema, consistent with Sweet's syndrome. Her symptoms resolved upon discontinuation of vemurafenib and treatment with prednisone. This constellation of symptoms and clinical course are consistent with drug‐induced Sweet's syndrome caused by vemurafenib.     

BRAF inhibitor‐associated cutaneous squamous cell carcinoma: new mechanistic insight,emerging evidence for viral involvement and perspectives on clinical management

Mutations in the BRAF proto‐oncogene occur in the majority of cutaneous melanomas. The commonly detected valine (V) to glutamate (E) mutation (V600E) is known to drive melanomagenesis and has thus been the target of two highly selective chemotherapeutic agents: vemurafenib and dabrafenib. While BRAF inhibitor therapy has revolutionized the treatment of metastatic melanoma, unanticipated cutaneous toxicities, including the development of cutaneous squamous cell carcinomas (cSCCs), are frequently reported and hinder therapeutic durability. However, the mechanisms by which BRAF inhibitors induce cutaneous neoplasms are poorly understood, thus posing a challenge for specific therapies. In this review, we summarize the clinical and molecular profiles of BRAF inhibitor‐associated cSCCs, with a focus on factors that may contribute to disease pathogenesis. In particular, we discuss the emerging evidence pointing towards viral involvement in BRAF inhibitor‐induced cutaneous neoplasms and offer new perspectives on future therapeutic interventions. Continued clinical and mechanistic studies along this line will not only allow for better understanding of the pathogenic progression of BRAF inhibitor‐induced cSCCs, but will also lead to development of new therapeutic and preventative options for patients receiving targeted cancer therapy.     

Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas

Vemurafenib, a selective BRAF (v‐raf murine sarcoma viral oncogene homologue B1) kinase inhibitor, is a new targeted biotherapy that improves survival in patients with metastatic melanomas harbouring the BRAF V600E mutation. However, this drug has significant dermatological adverse effects. We report a new severe cutaneous reaction to this drug associated with acute kidney injury (AKI). Four patients presented a generalized grade 3 (Common Terminology Criteria for Adverse Events) erythematous eruption with hyperkeratosis pilaris, 5–14 days after the introduction of vemurafenib. These symptoms were associated with AKI in all cases and transitory hypereosinophilia in two cases. Vemurafenib treatment was stopped in three patients and the dose was reduced in the fourth, leading to a gradual improvement of skin symptoms and renal function. Positron‐emission tomography scans showed a complete response in three cases and a major response in one case. Vemurafenib was reintroduced at a lower dose, without a relapse of the rash, but renal function again deteriorated. Thus, we report a cluster of four cases of AKI associated with similar, severe, grade 3 cutaneous drug reactions related to vemurafenib.     

Cutaneous side effects of TNF‐alpha inhibitors

Since the early 1990s, tumor necrosis factor alpha (TNF‐alpha) inhibitors have been successfully used in the treatment of various immune‐mediated inflammatory diseases. By now, comprehensive safety data has been compiled. While adverse reactions do occur, they are – in relation to the frequent use of these agents – rare and usually not serious. Cutaneous side effects include local injection site reactions, infections, immune‐mediated reactions, and neoplasms. The most common serious adverse events are of an infectious nature. Mycobacteria but also non‐mycobacterial pathogens, such as viruses and fungi, may cause serious, even lethal, systemic infections. The present article is meant to review current knowledge with respect to cutaneous side effects of TNF‐alpha inhibitors.     

Expanding the histologic findings in smallpox‐related post‐vaccinial non‐viral folliculitis

Post‐vaccinial non‐viral folliculitis has been recognized in the past decade as a new adverse cutaneous reaction to smallpox vaccination. Contrary to more serious smallpox vaccine reactions, post‐vaccinial non‐viral folliculitis has a benign course and resolves spontaneously within approximately 7 days. We describe additional histopathologic findings associated with post‐vaccinial non‐viral folliculitis, which has only been described once previously. New findings include the presence of a neutrophilic or lymphohistiocytic infiltrate that is concentrated around the hair follicles. We compare our findings to the follicular nature of varicella and herpes zoster infections, generating the hypothesis of deposition of vaccinia protein within folliculosebaceous units as a potential pathophysiologic mechanism behind post‐vaccinial non‐viral folliculitis.     

Intravesicular taxane‐induced dermatotoxicity in a 78‐year‐old man with urothelial carcinoma and primary cutaneous anaplastic large cell lymphoma

Patients treated with intravesical bacillus Calmette‐Guérin therapy for urothelial carcinoma often become refractory and experience recurrent disease, thus necessitating alternative intravesical treatment modalities if the patient is to be spared the morbidities associated with radical cystectomy. Intravesical treatment with taxane‐based chemotherapy, such as docetaxel, has gained traction in urologic oncology, proving to be an effective salvage therapy in such patients. Systemic taxane‐based chemotherapeutic regimens have long been used in several advanced malignancies, and their systemic side‐effects and associated histologic correlates have been extensively documented. In contrast to adverse effects associated with systemic administration, intravesical taxane administration has thus far proven to be well‐tolerated, with little to no systemic absorption. To our knowledge, features of taxane‐induced systemic effects have not been reported in this setting. Herein, we report a case of a patient with recurrent urothelial carcinoma treated with intravesical docetaxel, along with primary cutaneous anaplastic large cell lymphoma, who developed characteristic dermatotoxic histologic findings associated with intravenous taxane administration. As such histopathologic findings often represent close mimickers of neoplastic and infectious etiologies, knowledge of the potential for systemic manifestations of taxane therapy in patients treated topically may prevent potentially costly diagnostic pitfalls.     

Vemurafenib‐induced interface dermatitis manifesting as radiation‐recall and a keratosis pilaris‐like eruption

Vemurafenib is a specific inhibitor of the V600E mutated BRAF protein kinase used for the treatment of unresectable or metastatic melanoma harboring this mutation. Multiple predictable side effects have been described with use of this targeted therapy, and implicate BRAF and mitogen activated protein kinase (MAPK) signaling pathways in their pathogenesis. Herein, we report the novel finding of an interface dermatitis in radiation recall and a keratosis pilaris‐like clinical reaction in a patient treated with vemurafenib.     

Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management

Mutations in genes encoding for proteins along the RAS‐RAF‐MEK‐ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late‐stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar‐plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS‐RAF‐MEK‐ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management.     

Painful nipple hyperkeratosis secondary to vemurafenib

Vemurafenib is a selected BRAF kinase inhibitor approved for treating metastatic or unresectable melanoma, which has numerous cutaneous side effects unfortunately, including three previously reported cases of asymptomatic areola and/or nipple hyperkeratosis. We present the first case of painful bilateral nipple hyperkeratosis secondary to vemurafenib in an 84‐year‐old woman. She was successfully treated with tretinoin 0.05% cream that allowed her to comfortably continue treatment. With increased awareness of this condition, we found a second case of asymptomatic nipple hyperkeratosis secondary to vemurafenib in our clinic. As this medication gains acceptance for treatment of metastatic melanoma, it is imperative that dermatologists are aware of this potentially uncomfortable side effect that can result in decreased compliance and impaired quality of life.