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      Reintroduction of dabrafenib after previous vemurafenib-induced DRESS: Not always safe!

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      , MD, , MD, , MD, , MD, , MD
      JAAD Case Reports
      Elsevier

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          Abstract

          To the Editor: We read with interest the recent case report by Pinard et al 1 about the successful introduction of dabrafenib after DRESS (drug rash with eosinophilia and systemic symptoms) induced by vemurafenib and more recently the same successful experience of Tahseen et al 2 after vemurafenib-induced toxic epidermal necrolysis. However, from our own practice, we would caution that these experiences should not be extended to all patients. Indeed, we report the case of a patient with previous vemurafenib-induced DRESS in which this reintroduction has induced a recurrence of the hypersensitivity reaction. A 68-year-old man had a surgical resection of a nodular melanoma in the left abdominal region with a left inguinal lymphadenectomy. A positron emission tomography scan showed multiple adenopathies. A BRAF V600E mutation was identified, and vemurafenib was started in association with cobimetinib. Fourteen days later, the patient presented with facial erythema, cheilitis, maculopapular rash, intense pruritus, hyperthermia (39°C), and axillary and inguinal supracentimetric lymphadenopathies. No other drug had been introduced. Vemurafenib and cobimetinib were immediately discontinued. Laboratory tests found moderated hepatic cytolysis with aspartate aminotransferase 2N, Alanine transaminase 1,7N, but no evidence of renal failure. Polymerase chain reaction did not identify any viral reactivation (herpes simplex virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus-6, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, and HIV). Eosinophilia appeared (1.18 g/L) after 3 days. Skin biopsy findings supported the diagnosis of DRESS, revealing a moderate dermal lymphocytic infiltrate with eosinophils. DRESS syndrome was diagnosed according to the RegiSCAR international consensus criteria 3 with a score of 6. Oral corticosteroid therapy was initiated at 0.5 mg/kg/d, and the rash and blood parameters improved within 5 days and normalized within 2 weeks. Because of the benefit of BRAF inhibitors on his metastatic disease, and the published experience of the safe use of dabrafenib after previous SCAR (severe cutaneous adverse reaction) with vemurafenib, 4 dabrafenib was initiated 1 month later at the mild dose of 75 mg/d and carried out at the hospital with informed consent. Six hours after the first intake of dabrafenib, a maculopapular rash and hypereosinophilia (0.55 g/L) occurred. To prevent a recurrent potentially life-threatening DRESS that may have probably ensued, we decided to discontinue dabrafenib immediately and definitively. Immunotherapy with an anti–programmed cell death 1 agent was then started for the ongoing treatment of his metastatic melanoma. Contrary to what was suggested in both articles by Pinard et al 1 and Tahsen et al, 2 this case implies that the hypersensitivity reaction can be class specific rather than drug specific. Even if few cases noting the successful use of dabrafenib after vemurafenib-induced SCAR have been reported,1, 2, 4 the reintroduction cannot be alleged as safe and should be considered with care. In practice we do not suggest the avoidance dabrafenib after vemurafenib SCARs, but we emphasize that this introduction should take place within a hospitalized setting.

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          Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?

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            Successful switch to dabrafenib after vemurafenib-induced toxic epidermal necrolysis.

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              Successful use of dabrafenib after the occurrence of drug rash with eosinophilia and systemic symptoms (DRESS) induced by vemurafenib

              Introduction Vemurafenib and dabrafenib are 2 BRAF inhibitors that are approved by the US Food and Drug Administration for the treatment of metastatic malignant melanoma with BRAF mutation. These drugs improve overall- and progression-free survival. Some severe vemurafenib-induced reactions have been reported, which commonly require treatment withdrawal. We report the case of a patient with metastatic malignant melanoma in whom DRESS developed likely from vemurafenib. Because the patient did not respond to many previous treatments, dabrafenib, another BRAF inhibitor, was started without reoccurrence of DRESS. Case report A 46-year-old man with lentigo maligna melanoma of the ear (Breslow index, 1.71 mm) with V600E BRAF mutation was referred for lung, brain, liver, and subcutaneous metastases. He was treated previously with surgical excision of the external auditory meatus, complete parotidectomy, and carotid-jugular dissection. He was then treated with dacarbazine, temozolomide, and stereotactic radiotherapy when metastases occurred. Five years later, vemurafenib was started owing to progression of lung metastases. Twenty-one days later, the patient presented with a generalized maculopapular exanthema with facial edema. He had no fever or lymphadenopathy. Biological tests found blood eosinophilia (1.51 × 109/L), liver cytolysis (alanine aminotransferase, 717 U/L; aspartate aminotransferase, 323 U/L [normal range, 10-50 U/L]), and renal insufficiency (creatinine, 1.36 mg/dL [normal range, 0.7-1.2 mg/dL]). DRESS was diagnosed with a REGISCAR score of 6 of 8 points. 1 Because vemurafenib was the only drug taken by the patient, it was considered the culprit drug. Vemurafenib was stopped, and the patient was treated with topical corticosteroids and prednisone, 0.5 mg/kg/d initially, with a 20% tapering of the prednisone dose every 3 weeks, ending prednisone after 9 weeks. The patient's clinical condition and laboratory values improved within 2 weeks of vemurafenib withdrawal and start of corticosteroids. The patient was then treated with nivolumab (3 mg/kg twice a month) for 6 months and thereafter with ipilimumab (4 infusions of 3 mg/kg every 3 weeks) for 3 months. Because the diameter of the liver metastasis increased from 14 to 21 mm and a bone metastasis occurred on the sacral vertebra S1, dabrafenib was started after the patient gave informed consent. Dabrafenib was started at an initial dose of 75 mg/d, which was then gradually increased to 150 mg twice a day within 2 months (day 1, 75 mg; day 3, 150 mg; day 15, 225 mg; day 56, 300 mg). Dabrafenib was used alone without oral corticosteroids or antihistamines. DRESS symptoms did not reoccur, and the patient achieved partial remission after 3 months of follow-up. Discussion This case suggests the possibility of using dabrafenib in some patients who previously had a severe drug reaction induced by vemurafenib. This observation may have important implications because of the extremely severe course of metastatic malignant melanoma after vemurafenib withdrawal. Additionally, it suggests that DRESS reaction to these medications may be drug specific as opposed to class specific. The frequency of nonsevere eruptions induced by vemurafenib is estimated between 32% and 64%. 2 Several studies found the possibility of gradually rechallenging vemurafenib after the occurrence of a nonsevere eruption with no visceral involvement. 3 Four cases of DRESS and 3 cases of Stevens-Johnson syndrome induced by vemurafenib, but none by dabrafenib, have been reported.4, 5 The successful use of dabrafenib in a case of vemurafenib-induced Stevens-Johnson syndrome has been reported. 6 The regimen of dabrafenib used in this report consisted of 10 mg on day 1, 20 mg on day 2, 30 mg on day 3, 75 mg on day 4, 150 mg on day 5, 150 mg on day 6, and 300 mg/d thereafter. 6 The absence of severe drug-induced reaction with dabrafenib and the absence of reoccurrence of symptoms after switching from vemurafenib to dabrafenib in our case of DRESS along with the previously reported case of Stevens-Johnson syndrome, suggest that these medications may be drug specific as opposed to class specific. The P-glycoprotein might be involved in the difference observed between vemurafenib and dabrafenib. Indeed, several in vitro studies found that vemurafenib was both substrate (poor) and inhibitor of the P-glycoprotein, 7 whereas dabrafenib was only substrate of the P-glycoprotein. 8 One can hypothesize that this difference between the 2 BRAF inhibitors might explain the higher incidence of severe adverse effects reported withs vemurafenib than with dabrafenib. This finding might be related to the inhibition of the drug excretion, resulting in an increase in the plasma concentration of vemurafenib. Overall, our observation suggests the possibility of using dabrafenib in some patients who previously had DRESS from vemurafenib and did not respond to other melanoma treatments. Patients must be informed about the risk of such a switch among the same drug class.
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                Author and article information

                Contributors
                Journal
                JAAD Case Rep
                JAAD Case Rep
                JAAD Case Reports
                Elsevier
                2352-5126
                28 April 2019
                May 2019
                28 April 2019
                : 5
                : 5
                : 422-423
                Affiliations
                [1]Saint André Hospital, University Hospital Center of Bordeaux, Bordeaux, France
                Author notes
                []Correspondence to: Brigitte Milpied, MD, Saint André Hospital, University hospital center of Bordeaux, 1 rue Jean Burguet, 33000 Bordeaux, France brigitte.milpied@ 123456chu-bordeaux.fr
                Article
                S2352-5126(19)30101-8
                10.1016/j.jdcr.2019.02.033
                6488678
                3533b6bc-d1e3-4049-9f87-abca860f4868
                © 2019 Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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