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Dramatic transient improvement of metastatic BRAFV600E-mutated Langerhans cell sarcoma under treatment with dabrafenib

Samia Mourah, Gwenaël Lorillon, Véronique Meignin, Laetitia Vercellino, Constance de Margerie-Mellon, Cécile Pages, Lauriane Goldwirt, Alexandre How-Kit, Jorg Tost, Céleste Lebbe and Abdellatif Tazi

To the editor:

Langerhans cell sarcoma (LCS) is a rare histiocytic neoplasm with overt malignant cytological features and an aggressive clinical course.1 Disseminated LCS carries a poor prognosis.1 We report a case of a metastatic BRAFV600E-mutated LCS that dramatically improved after administration of the BRAF inhibitor (BRAFi) dabrafenib.

A 58-year-old man was referred in August 2014 with a diagnosis of progressive Langerhans cell histiocytosis (LCH). He was treated in July 2013 by surgery and radiotherapy for left humerus LCH diagnosed by bone biopsy. In February 2014, enlargement of the left axillary, pectoral, and supraclavicular lymph nodes was observed. Histologic examination of a lymph node biopsy indicated LCH recurrence, although some atypical cells were described. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy was initiated but was discontinued after 3 cycles because of disease progression. The patient’s condition deteriorated. The lymph nodes increased in size and multiple lung nodules were observed on lung computed tomography (CT) scan. These lesions were highly hypermetabolic on fluorodeoxyglucose (18-FDG) positron emission tomography (PET)-CT (Figure 1). A new lymph node biopsy revealed massive infiltration by very large cells with irregular folded nuclei and necrotic areas. The mitotic rate was >50 per 10 high-power fields. The tumor cells expressed CD1a and langerin (Figure 1), features characteristic of LCS.1,2 A review of previous biopsies showed the presence of small areas of similar tumor cells. All tissue specimens harbored the BRAFV600E mutation, as determined by immunohistochemistry and molecular genotyping (Figure 1). After informed consent, dabrafenib (150 mg twice daily) was initiated. Within a week, the patient improved, and the lymph nodes dramatically decreased in size. A lymph node biopsy performed on treatment day 10 showed massive necrosis of tumor cells and the absence of the BRAFV600E mutation (Figure 1). Serial 18-FDG PET-CT scans after 3 months of treatment revealed marked improvement of the lesions, with residual small axillary adenopathy (Figure 1). The patient was in complete response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and in partial metabolic response according to European Organisation for Research and Treatment of Cancer (EORTC) criteria. The treatment was well tolerated except for diarrhea (which resolved after the dabrafenib dose was reduced to 100 mg twice daily) and palmoplantar hyperkeratosis. Average values of dabrafenib plasma trough and maximal concentrations, which were monitored monthly, reached 16 ng/mL (15-27 ng/mL) and 604 ng/mL (507-786 ng/mL), respectively, consistent with previous pharmacokinetic studies.3

Figure 1

BRAFV600 genotyping. (A) 18-FDG PET-CT before the onset of treatment. (a) Fused PET-CT axial view of pulmonary nodules (standardized maximal uptake [SUVmax] = 12). (b) Left axillary mass (SUVmax = 11.9). 18-FDG PET-CT after 3 months of dabrafenib treatment. (c) Fused PET-CT showing no significant residual uptake in the lung. (d) Presence of a residual small axillary lymph node with decreased uptake (SUVmax = 4.5). The patient was classified as partial metabolic response according to the EORTC criteria (ie, >25% reduction of the SUVmax in the target lesions), with a decrease in SUVmax of 83% in the target lesions. 18-FDG PET-CT after 6 months of dabrafenib treatment at the time of LCS relapse. (e) Fused PET-CT showing a hypermetabolic pulmonary nodule (SUVmax = 6.3) and mediastinal lymph nodes (SUVmax = 8.7); (f) axillary nodal relapse (SUVmax = 9.6). (B) Light optic microscopy of the left axillary lymph node biopsy before and during treatment. (a) Hematoxylin-and-eosin (HE) staining showing a very pleomorphic proliferation composed of large tumor cells with folded nuclei, and numerous mitotic cells. (b) Tumor cells stained with an anti-CD1a antibody (clone O10; Dako); (c) most of the cells are langerin (CD207)-positive (clone 12D6; Novocastra). These features are characteristic of LCS. (d) Anti-BRAFV600E (clone VE1; Spring Biosciences) immunostaining is positive in tumor cells. (e) HE staining of a lymph node biopsy at day 10 of dabrafenib treatment, showing massive necrosis of tumor cells. (f) No cells stained positive with the anti-BRAFV600E mutation-specific antibody. Original magnification, ×400 in all sections. (C) Pyrosequencing of DNA extracted from lymph node biopsies. (a) Before treatment, the BRAFV600E mutation is present (mutated allele = 78%); (b) on day 10 of dabrafenib treatment, only wild-type BRAFV600 is observed (mutated allele = 1.4%); and (c) at the time of LCS recurrence, demonstrating the resurgence of the BRAFV600E mutation (mutated allele = 52%). (D) Expression of MAP3K8/COT protein in the pretreatment and relapsing tumor. HT-29 BRAFV600E colorectal cells that express both the long (1-467) and short (30-467) forms of COT are shown as a positive control. β-actin served as loading control. Extracellular signal-regulated kinase (ERK) expression and activation in relapsed LCS. (E) Tumor cells are intensively stained with an anti-phospho-ERK-1/2 antibody (clone MAPK-YT; Sigma) compared with pretreatment tumor cells. Original magnification, ×400. (F) Western blot analysis for phosphorylated ERK (pERK) and ERK (endogenous total ERK) in the pretreatment and relapsing tumors is shown. A375 BRAFV600E melanoma cells were used as a positive control.

At 6 months, 18-FDG PET-CT revealed an increase in size of the left axillary lymph node, the enlargement of mediastinal lymph nodes, and a left pulmonary nodule (Figure 1). The axillary lymph node biopsy confirmed the recurrence of BRAFV600E-mutated LCS (Figure 1). To determine the mechanisms by which dabrafenib resistance was acquired, genomic and transcriptomic analyses of the main previously described factors involved in BRAFi resistance were performed on the pretreatment and relapsing tumors, which contained 95% and 90% tumor cells, respectively4-6 (supplemental Methods and supplemental Table 1, see supplemental Data available on the Blood Web site). No NRASG12/G13/Q61, KRASG12/G13, or MAP2K1 (exons 2 and 3) mutations or BRAF splicing variants were detected in the recurrent lesion.4-6 The MAP3K8/COT messenger RNA level, normalized to the number of tumor cells, was threefold (3.3 ± 0.2) increased in the relapsing specimen as compared with the initial tumor. This increase, which was also observed at the protein level, may explain the observed intense activation of the mitogen-activated protein kinase (MAPK) pathway (Figure 1). Indeed, in melanoma, MAP3K8/COT overexpression drives resistance to BRAFi through MAPK pathway reactivation which may be overcome by the addition of a MAPK kinase inhibitor (MEKi).4 The patient was thereafter switched to combined vemurafenib and cobimetinib treatment. Within 3 days, the patient clinically improved. At 10 weeks of treatment, he had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 and the different tumor localizations had decreased in size.

LCS is a rare malignant histiocytic disorder that affects the lymph nodes as well as extranodal sites.1 LCS is differentiated from LCH based on cytological criteria, a high mitotic index, and more aggressive behavior.1,2 Various chemotherapy regimens, primarily CHOP, are used with limited response rates and high mortality.1 Recently, the BRAFV600E mutation was identified in a variable proportion of dendritic cell neoplasms, including LCS, suggesting that these patients may benefit from BRAFi.1,7,8 The dramatic response of the present case to dabrafenib further supports the key role of the BRAFV600E mutation in histiocytic disorders,9,10 although secondary resistance to BRAFi treatment may occur in malignant forms.8

In melanoma, a first-line therapeutic strategy with the combination of BRAFi and MEKi has been demonstrated to prevent or delay the onset of resistance observed with treatment with BRAFi alone, in addition to increasing progression-free survival.11,12 A similar strategy might be more appropriate in progressive BRAFV600E-mutated histiocytic malignancies.

Authorship

Acknowledgments: The authors thank Aurélie Sadoux, Coralie Reger de Moura (Laboratoire de Pharmacologie Biologique, Hôpital Saint-Louis, Paris, France), and Maeva Valluci (Centre National de Référence de l’Histiocytose Langerhansienne, Service de Pneumologie, Hôpital Saint-Louis, Paris, France) for technical support, and Elisabeth Savariau (Institut Universitaire d’Hématologie, Service d’Infographie, Hôpital Saint-Louis, Paris, France) for assistance with the figures.

Contribution: S.M. and A.T. designed the research, analyzed and interpreted the data, and wrote the manuscript; G.L. managed sample acquisition and collected clinical data; V.M. analyzed and interpreted histologic data; L.V. analyzed and interpreted 18-FDG PET-CT findings; C.d.M.-M. analyzed and interpreted radiologic results; C.P. analyzed and interpreted dermatologic clinical findings; L.G. analyzed and interpreted pharmacologic data; A.H.-K. and J.T. analyzed BRAF, NRAS, and KRAS genotyping and interpreted the data; and C.L. provided expertise in the melanoma field and intellectual content.

Conflict-of-interest disclosure: S.M. declares a consulting role for Roche and Novartis. C.d.M.-M. declares travel accommodation by Guerbet. L.G. declares travel accommodation by Janssen. C.L. declares honoraria from Roche, advisory roles for Roche, GlaxoSmithKline (GSK), Novartis, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), and Amgen, and travel accommodation by Roche. The remaining authors declare no competing financial interests.

Correspondence: Abdellatif Tazi, Service de Pneumologie, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475, Paris cedex 10, France; e-mail: abdellatif.tazi{at}sls.aphp.fr.

Footnotes

  • The online version of this article contains a data supplement.

References