Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation (2014)

To the Editor: We report the case of a female patient in her 90s with a history of age-related macular degeneration and pulmonary embolism. In 2011, she presented with pruritic, erythematous, confluent, maculopapular skin lesions located on the trunk, inframammary fold, groin, and genital and perianal areas. Histology of a skin biopsy revealed a mononuclear cell infiltrate that was morphologically and phenotypically consistent with Langerhans cell histiocytosis (LCH) expressing CD1a and S100-protein by immunohistochemistry. A body computed tomography scan showed no visceral involvement, the patient had no exophthalmos or diabetes insipidus, and laboratory tests related to LCH secondary localizations were normal (eg, inflammatory and hepatic markers, hemogram). Subsequently, a diagnosis of single system cutaneous LCH was established. Topical and systemic corticosteroid treatments failed to elicit any clinical improvement as first-line treatment, and the patient was suffering from chronic and severe pruritus and pain, affecting her quality of life that declined significantly. A second line of systemic treatment with thalidomide was initiated but was quickly discontinued because the patient experienced minor clinical response with major side effects such as dizziness, asthenia, and impaired coordination. Recently, she experienced a severe new flare of her disease with multiple papulonodular lesions in the same skin areas (Fig 1, before). The patient complained of major pain and had suicidal ideation related to her intolerable skin discomfort. No extracutaneous involvement was found, and a new biopsy confirmed the diagnosis of widespread single system cutaneous LCH (Fig 2, A-C). In conjunction with this finding, the DNA from the biopsy was extracted and a pyrosequencing analysis revealed a BRAF V600E mutation, as expected for up to 57% of LCH cases.1Badalian-Very G. Vergilio J.A. Degar B.A. MacConaill L.E. Brandner B. Calicchio M.L. et al.Recurrent BRAF mutations in Langerhans cell histiocytosis.Blood. 2010; 116: 1919-1923Crossref PubMed Scopus (761) Google Scholar After a multidisciplinary consultation, she was started on a third-line vemurafenib treatment, (960 mg orally twice a day) immediately after obtaining written informed consent. Vemurafenib induced a major clinical improvement in the first days of treatment. The patient was seen for follow-up 3 weeks after vemurafenib introduction and showed indisputable regression of her cutaneous lesions. Moreover, histopathologic and immunohistochemical studies confirmed the clinical response, in that a new biopsy revealed the absence of remaining cells expressing LCH markers (Fig 2, D and E) . After the third month of treatment, the clinical response remained stable and after 6 months of vemurafenib, only scar tissue was noticeable (Fig 1, after). Vemurafenib is an anti-BRAF targeted therapy approved for the treatment of metastatic unresectable melanoma with V600 mutations; sensitivity to this molecule was recently demonstrated for BRAF mutated non-LCH (ie, CD1- negative Erdheim-Chester disease).2Haroche J. Cohen-Aubart F. Emile J.F. Arnaud L. Maksud P. Charlotte F. et al.Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.Blood. 2013; 121: 1495-1500Crossref PubMed Scopus (390) Google Scholar Here we report a major clinical response to vemurafenib for refractory, widespread, skin-limited, pure LCH carrying the BRAF V600E mutation. According to other frequent localizations of LCH, it would also be important to evaluate whether vemurafenib can diffuse and be effective in bones and brain. The rapid response and remarkable efficacy of vemurafenib in this case should encourage practitioners to perform systematic BRAF gene mutation testing for LCH patients. These results also suggest that this strategy could become a new gold standard first-line treatment for BRAF V600E LCH after further validation in prospective multicenter trials. We thank Dr Lucie Sancey, PhD, for expert graphical artwork and Dr Stratton Beatrous, MD, for manuscript revision. Vemurafenib as first line therapy in BRAF-mutated Langerhans cell histiocytosisJournal of the American Academy of DermatologyVol. 73Issue 1PreviewTo the Editor: We read with great interest the letter by Charles et al: “Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation.” This case report confirms our study in 2013 of 3 patients with refractory BRAFV600E mutated Erdheim-Chester disease (ECD), 2 of whom also had Langerhans cell histiocytosis (LCH).1 We observed that vemurafenib was very effective against the LCH component of the disease in our patients (which was much less pronounced than in the case reported recently) in the short-term, with disappearance of the cutaneous LCH lesions within a few days. Full-Text PDF