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Vemurafenib-associated neutrophilic panniculitis: An emergent adverse effect of variable severity

  • Author(s): Maldonado-Seral, Cayetana
  • Berros-Fombella, Jose Pablo
  • Vivanco-Allende, Blanca
  • Coto-Segura, Pablo
  • Vazquez-Lopez, Francisco
  • Perez-Oliva, Narciso
  • et al.
Main Content

Vemurafenib-associated neutrophilic panniculitis: An emergent adverse effect of variable severity
Cayetana Maldonado-Seral MD, Jose Pablo Berros-Fombella MD, Blanca Vivanco-Allende MD, Pablo Coto-Segura MD, Francisco Vazquez-Lopez MD, Narciso Perez-Oliva MD
Dermatology Online Journal 19 (4): 16



Abstract

Vemurafenib is a selective BRAF kinase inhibitor recently proven to improve rates of overall and progression-free survival in patients with BRAF-V600-mutant metastatic melanoma. The most common adverse effects of this targeted therapy are arthralgia, fatigue, and cutaneous lesions, including alopecia, photosensitivity, pruritus, hand-foot skin reactions, squamous cell carcinomas, keratoacanthomas, warty dyskeratomas and verrucous keratosis. Less frequently, cases of panniculitis of varying severity have been reported in patients receiving vemurafenib. In this report, we describe a patient who developed asymptomatic nodules on her legs, with complete, spontaneous resolution, while on vemurafenib therapy. A causal relationship was considered likely because of the timing of occurrence and the absence of other potential causes after extensive assessment. Vemurafenib therapy was continued at full dosage and no recurrences were observed. We believe that management of lobular panniculitis associated with selective BRAF inhibitors should vary according to the clinical presentation, degree of systemic involvement, and presence of joint inflammation. Physicians should be aware of this emergent side effect. Treatment discontinuation should be considered on a case-by-case basis because the condition may resolve spontaneously.



Introduction

In patients with metastatic melanoma harboring BRAF mutations, treatment with the selective BRAF inhibitor vemurafenib has resulted in improved rates of overall and progression-free survival [1, 2]. Painful panniculitis with arthralgia has been reported in two patients with metastatic melanoma treated with selective BRAF inhibitors [3]. Recently, Monfort et al reported two additional cases of neutrophilic panniculitis occurring in melanoma patients receiving vemurafenib [4]. We report a new patient in whom this adverse event developed. The patient was asymptomatic and panniculitis resolved spontaneously despite continued vemurafenib therapy.


Case report


Figure 1Figure 2
Figure 1. Erythematous subcutaneous nodules on both thighs

Figure 2. Neutrophilic panniculitis

A 42-year-old woman presented to our department in 2012 with a presumptive diagnosis of lung metastases from a melanoma on her back, which had been removed at another hospital in 2004. The pulmonary lesions were surgically resected and a diagnosis of metastatic melanoma was confirmed histopathologically. Molecular analysis of the lung metastases showed a BRAFV600E mutation. Positron emission tomography/computed tomography (PET-CT) imaging was performed after the surgery and revealed a positive mediastinal lymph node. The patient was selected for targeted therapy with the oral selective BRAF inhibitor vemurafenib, which was given at a dose of 940 mg twice daily within an expanded-access phase III clinical trial. Two weeks later, she suddenly developed asymptomatic nodules on her legs. There was no arthralgia, joint swelling, fever, pain, or any other symptoms, and no limitation of her activities of daily living. The patient did not report use of any other new drugs or symptoms of acute infection preceding appearance of the nodules. Physical examination revealed several erythematous subcutaneous nodules, 1–2 cm in diameter and non-tender to palpation, on both thighs (Figure 1). There was no joint swelling or any other physical signs. A routine laboratory workup, including C-reactive protein, antinuclear antibody, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, complement components C3 and C4, and alpha 1-antitrypsin, was within normal limits. Biopsy of the lesions revealed a lobular panniculitis with predominant neutrophil and histiocytic infiltration and no vasculitis (Figure 2). There was no evidence of bacterial infection, melanophages, malignancy, or atypia. Melan-A and S100 staining were negative. The patient was diagnosed with lobular panniculitis likely related to vemurafenib therapy and classified as a grade 1 event under the Common Terminology Criteria for Adverse Events, v4.0 (CTCAE) [5]. Vemurafenib was continued at full dose. Anti-inflammatory drugs were not prescribed. In the space of a few days, the skin nodules gradually subsided and eventually resolved completely. No recurrence was observed. However, a biopsy-proven squamous cell carcinoma, 0.5 cm in diameter, was removed from her left eyelid after two months of treatment.


Discussion

Lobular panniculitis can be associated with a variety of underlying conditions or may be idiopathic. In the case reported herein, the differential diagnosis included inflammatory metastases of melanoma, infectious panniculitis, traumatic panniculitis, alpha 1-antitrypsin deficiency, pancreatic panniculitis, neutrophilic dermatosis, factitial panniculitis, panniculitis associated with other drugs, and other forms of panniculitis. All of these causes were ruled out. In this case, we considered a causal relationship with vemurafenib to be likely because of the timing of onset, the absence of other possible causes and the existence of four other previously reported cases of panniculitis related to BRAF inhibitor therapy [3, 4].

Vemurafenib is generally considered to be well tolerated, but adverse effects may occur. In clinical trials, case series and case reports, the most common adverse events of vemurafenib were arthralgia, fatigue and cutaneous lesions, including alopecia, photosensitivity, pruritus, hand-foot skin reactions, cutaneous eruptions (keratosis pilaris-like eruptions, seborrheic dermatitis-like eruptions, Darier or Grover-like eruptions), darkening of existing nevi, and new nevi [1-9]. Development of malignant and benign hyperproliferative skin lesions (squamous cell carcinomas, keratoacanthoma, warty dyskeratomas, and verrucous keratosis) has also been documented. Many of these adverse events are reminiscent of those associated with the broad-spectrum RAF inhibitor sorafenib [6].

Zimmer et al reported two cases of symptomatic, painful, lobular panniculitis with arthralgia in women receiving selective BRAF inhibitor therapy for metastatic melanoma [3]. The same report cited the case of a patient who developed symptomatic, recurrent, neutrophilic panniculitis and fever while undergoing combined treatment with dabrafenib (a selective BRAF inhibitor) and trametinib (a MEK inhibitor). More recently, Monfort et al reported two additional cases [4] and Sinha et al observed two patients with erythema nodosum-like lesions [9].

The two patients reported by Zimmer et al were highly symptomatic, had arthralgia or joint swelling, and required treatment with oral prednisolone and/or nonsteroidal anti-inflammatory drugs (NSAIDs). One eventually required discontinuation and subsequent dose reduction of the BRAF inhibitor (CTCAE grade 3 event) [3]. The two cases reported by Monfort et al were classified as CTCAE grade 2 and vemurafenib treatment was continued. Lesions improved spontaneously without steroids or NSAIDs [4]. The patients observed by Sinha et al required a 3-to-4 day break in treatment and no specific treatment for the panniculitis [9].

Our patient was completely asymptomatic and her panniculitis resolved spontaneously; therefore, it was classified as a CTCAE grade 1 reaction. Zimmer et al suggested early treatment with nonsteroidal anti-inflammatory drugs and even a reduction in the dose of vemurafenib as the treatment of choice for panniculitis in these patients [3]. We suggest that management of lobular panniculitis associated with selective BRAF inhibitor therapy should vary according to clinical presentation, degree of systemic involvement, and presence of joint inflammation. Pharmacological treatment is not always required in patients with lobular panniculitis secondary to vemurafenib therapy because it may resolve spontaneously. The decision to discontinue treatment should be made on a case-by-case basis after assessment of symptom severity.

References

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