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Drug rash with eosinophilia and systemic symptoms (DRESS) due to vemurafenib plus cobimetinib for metastatic melanoma

This is a case-report of a patient with BRAF-mutant metastatic melanoma diagnosed with severe systemic hypersensitivity reaction due to the combined treatment with vemurafenib and cobimetinib. Patient’s primary melanoma was excised from the skin of presternal region in 2010 (pT2a, Breslow 1.8 mm), followed by reexcision and sentinel lymph node biopsy which was negative. In October 2020, the patient has been diagnosed with metastases in a conglomerate of pathologically enlarged mediastinal lymph nodes based on PET-CT scan and treatment with vemurafenib and cobimetinib was started. On day 10 from the introduction of therapy, the patient developed a rash accompanied by subfebrile temperature and sore throat. Upon admission, there was generalized erythematous maculopapular rash, more severely affecting the face, trunk and upper extremities with erosive cheilitis and eyelids edema. On the third day of hospitalization, there was craniocaudal progression and confluence of the rash covering 80% of the body surface area, with multiple targetoid lesions, but without necrolysis or bullae. Also, the conjunctiva was gently injected and several tiny crusts were observed on the lower lip. Laboratory findings showed thrombocytopenia, lymphocytopenia, mild eosinophilia, anemia, elevated C-reactive protein, signs of hepatitis with elevated liver parameters but negative serology for HBV and HCV. There were also signs of nephritis - microhematuria and proteinuria with new-onset hypertension. With prompt withdrawal of causative drugs and treatment with systemic corticosteroids and supportive measures, gradual but complete regression of the rash and normalization of complete blood count, liver, renal and inflammatory parameters were achieved over the course of the following 4 weeks. The clinical course was complicated by the development of right-sided pneumonia and staphylococcal bacteremia, which were treated with parenteral antibiotic therapy for 12 days. Based on the clinical presentation and the results of the tests performed, a diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) caused by BRAF/MEK inhibitors vemurafenib and cobimetinib was made. Following the recovery, the patient has been successfully transitioned to dabrafenib plus trametinib with no reoccurrence of the skin rash or affection of any of the internal organs. Although targeted therapy with BRAF and MEK inhibitors represents an effective treatment option for patients with advanced BRAF-mutant melanoma, this case highlights the possibility of severe toxicity induced by vemurafenib plus cobimetinib and the need for watchful follow-up of this patient population with the aim of early recognition of severe, grade 4, potentially fatal, cutaneous adverse reactions requiring prompt withdrawal of the offending drugs and timely introduction of systemic corticosteroid therapy.

Drug rash ; metastatic melanoma ; vemurafenib ; cobimetinib ; hepatitis ; nephritis

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