Dramatic response to encorafenib in a patient with <scp>E</scp>rdheim–<scp>C</scp>hester disease harboring the <scp><i>BRAF</i><sup>V600E</sup></scp> mutation
Authors: Fumiya Wada, Nobuhiro Hiramoto, Daisuke Yamashita, Shigeo Hara, Yutaka Furukawa, Junko Ishii, Kazuma Nagata, Yasuhito Nannya, Seishi Ogawa, Takayuki Ishikawa
Journal: American Journal of Hematology (2021)

Erdheim–Chester disease (ECD) is a rare, non-Langerhans histiocytosis characterized by infiltration of foamy histiocytes positive for CD68 and negative for CD1a, as shown on immunostaining. Clinical manifestations include long-bone osteosclerosis, cardiovascular involvement, retroperitoneal fibrosis, endocrinopathies, xanthelasma, and neurological disability. Mutations in the MAPK pathway have been observed in more than 80% of patients with ECD, mainly including the BRAFV600E mutation in 57% to 70% of patients.1, 2 According to the consensus recommendations for the treatment of ECD, the use of BRAF inhibitors should be strongly considered in patients with life-threatening cardiological and neurological symptoms. The BRAF inhibitors such as vemurafenib, dabrafenib, and encorafenib are used in clinical practice for the treatment of patients with advanced melanoma harboring the BRAFV600E mutation. Although patients with ECD harboring the BRAFV600E mutation have been successfully treated with vemurafenib or dabrafenib,3, 4 there are no available studies to date on the use of encorafenib. Encorafenib is the newest BRAF inhibitor, which shows pharmacological properties distinct from those of vemurafenib or dabrafenib. Encorafenib showed a better progression-free survival (PFS) than vemurafenib in a phase III trial conducted in patients with advanced melanoma harboring the BRAFV600E mutation.5 Herein, we describe the first case of a patient with ECD harboring the BRAFV600E mutation treated with encorafenib. Encorafenib showed dramatic efficacy in patients with ECD and life-threatening neurological symptoms. An 81-year-old woman was admitted to our hospital in October 2018. She presented with dyspnea on exertion due to pericardial effusion. She had no relevant medical history. Radiological imaging revealed pericardial effusion with pericardial thickening, sheathing of the thoracic and abdominal aorta, retroperitoneal fibrosis, and bilateral symmetrical osteosclerosis of the femur, tibia, and fibula. Cytological examination of the pericardial effusion and histological examination of the retroperitoneal tissue failed to provide a definitive diagnosis. However, we strongly suspected ECD based on the specific clinical features. Her respiratory symptoms resolved by aspiration of pericardial fluid and treatment with diuretics. She was followed up in an outpatient setting. Two years later, the patient presented to the emergency department with dyspnea at rest due to left pleural effusion and pleural thickening. She also experienced persistent headache, requiring analgesic treatment. Note, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scan showed FDG uptake in the left pleural cavity, thoracic and abdominal aorta, retroperitoneal tissues, and bilateral leg bones (Figure 1(A)). Magnetic resonance imaging (MRI) of the head revealed a mass measuring 21 mm in diameter covering the vertebral artery and compressing the brainstem (Figure 1(C)). Thoracoscopic biopsy of the pleural specimen showed infiltration of typically foamy histiocytes mixed with inflammatory cells and fibrosis. Immunohistochemical staining showed that the histiocytes were positive for CD68 and BRAF V600E (clone: VE1) but negative for CD1a (Figure S1). The DNA extracted from the pleural specimens was analyzed for targeted gene sequencing of 377 recurrently mutated genes in myeloid neoplasms, and the BRAF c.1799T>A (p.V600E) mutation with a variant allele frequency of 0.059 was identified. Our treatment strategy included BRAF inhibitors, owing to the occurrence of life-threatening neurological symptoms. Since the use of BRAF inhibitors for the treatment of ECD is not covered by the Japanese insurance system, we obtained informed consent from the patient and approval of the ethics committee for the use of encorafenib. The patient was administered oral encorafenib (100 mg) once daily, which is one-third of the US Food and Drug Administration (FDA)-approved dose as monotherapy for melanoma. A few weeks later, the patient's dyspnea and headache were completely relieved. After 3 months of encorafenib treatment, MRI of the head revealed a 40% reduction in the size of the mass compressing the brainstem. After 6 months of treatment, 18F-FDG-PET/CT showed complete metabolic remission of ECD according to the PET Response Criteria in Solid Tumors (Figure 1(B)), and MRI of the head showed partial remission of the mass (Figure 1(D)). The adverse events related to the treatment with encorafenib were grade 2 palmar-plantar erythrodysesthesia syndrome (PEES), myalgia, and grade 1 alopecia, which gradually developed a month after the initiation of encorafenib treatment. The daily dose of encorafenib was reduced to 50 mg, 2 months after treatment initiation because of the occurrence of PEES and myalgia. One month after dose reduction, the adverse events gradually resolved, allowing for dose readjustment back to the initial dose (100 mg daily), which is being continued to date. The BRAF inhibitors have shown promising efficacy in patients with melanoma harboring the BRAFV600E mutation. Also, BRAF inhibitors such as vemurafenib, dabrafenib, and encorafenib have been approved by the US FDA for use in the treatment of patients with melanoma harboring the BRAFV600E mutation. By contrast, only vemurafenib has been approved for the treatment of patients with ECD harboring the BRAFV600E mutation, based on the results of a previous phase II trial.3 However, the other newer BRAF inhibitors could not be approved for the treatment of ECD, which is an extremely rare disease, and the conduct of clinical trials to investigate rare disorders is inherently difficult. Unfortunately, BRAF inhibitors have not been approved for use in the treatment of patients with ECD harboring the BRAFV600E mutation both in Japan and Europe, where there is orphan drug designation. In the above mentioned phase II trial, most patients with ECD required dose reduction or discontinuation of vemurafenib because of the occurrence of adverse events.3 Although no studies have provided a direct comparison between vemurafenib and dabrafenib, several studies investigating melanoma have shown a lower incidence of adverse events in patients receiving dabrafenib than in those receiving vemurafenib. Considering these aspects, Bhatia et al. reported a case series of 11 patients with ECD harboring the BRAFV600E mutation and treated with dabrafenib, which showed consistent efficacy in both newly diagnosed and refractory diseases.4 However, to date, no study has reported the use of encorafenib in patients with ECD harboring the BRAFV600E mutation. Development of newer BRAF inhibitors with increased efficacy is anticipated to decrease the incidence of adverse events. Encorafenib is the newest BRAF inhibitor approved by the FDA for the treatment of patients with melanoma harboring the BRAFV600E mutation. Encorafenib has a pharmacologic profile distinct from that of vemurafenib or dabrafenib; encorafenib suppresses the BRAFV600E activity at similar concentrations with a more than 10-times longer dissociation half-time than do vemurafenib or dabrafenib. This enables sustained inhibition of the target and reduced adverse events arising from paradoxical activation of the MAPK pathways in normal tissues.6 In a phase III trial for advanced melanoma, encorafenib showed an overall response rate of 52% with a median PFS of 9.6 months, which is longer than that reported for vemurafenib (7.3 months) and dabrafenib (8.8 months).5, 7 In addition, the incidence rate of grade 3 to 4 secondary cutaneous malignancy arising from the paradoxical activation of the MAPK pathways due to treatment with encorafenib was 0%, markedly lower than that with vemurafenib (7%) and dabrafenib (9%).5 Haroche et al. reported the sustained efficacy of targeted therapy with vemurafenib in a first case series of eight patients with ECD harboring the BRAFV600E mutation.8 Although the first four patients were treated with 960 mg of vemurafenib twice a day, which corresponds to the FDA-approved dose for patients with melanoma, the treatment dosage had to be reduced to 480 mg twice a day because of severe cutaneous adverse events. Therefore, vemurafenib was administered at a dose of 480 mg twice daily to other patients. However, all patients developed grade 2–3 severe skin adverse events despite reducing the dose by half of the approved dose. Several other studies have also reported that the FDA-approved dose of vemurafenib is either not practical or sustainable because of the occurrence of adverse events, which can lead to dose reduction or discontinuation.3 Therefore, the latest consensus guidelines for the management of ECD recommend that the initial dose of BRAF inhibitors (vemurafenib or dabrafenib) should be 25–50% of the FDA-approved dose. In the phase III trial for advanced melanoma mentioned earlier, adverse events requiring dose adjustment or interruption of encorafenib were reported in 71% of patients.5 Considering these aspects, we administered an initial dose of 100 mg once daily, which is one-third of the FDA-approved dose of encorafenib for melanoma. However, the patient required further dose reduction because of the occurrence of PEES and alopecia, which were common adverse events occurring in 52% and 56% of patients treated with encorafenib, respectively. In contrast, treatment with vemurafenib and dabrafenib has associated molecule-specific adverse events. These include photosensitivity (vemurafenib) and pyrexia (vemurafenib and dabrafenib), which are less frequently observed with encorafenib (Table S1). In conclusion, we describe the first case of a patient with ECD harboring the BRAFV600E mutation and treated with encorafenib. Encorafenib demonstrated dramatic efficacy in patients with life-threatening neurological symptoms despite the administration of one-third of the FDA-approved dose for melanoma. The results of this case report suggest that further studies are warranted to elucidate the efficacy of encorafenib as an alternative BRAF inhibitor in patients with ECD harboring the BRAFV600E mutation. The authors would like to thank the medical and nursing staff at our institution. The analysis of gene sequences was supported by the Ministry of Education, Culture, Sports, Science and Technology under Grant Number hp160219 and by the Agency for Medical Research and Development (AMED) under Grant Number JP20cm0106501h0005 to S.O. (Seishi Ogawa). The authors declare no conflict of interest. Informed consent was obtained from the patient. Data sharing is not applicable to this article, as no new data were created or analyzed in this study. Figure S1. Histological findings of the pleura. (A) The lesion shows infiltration of typically foamy histiocytes mixed with inflammatory cells and fibrosis (H&E staining, ×400). (B) Positive immunostaining for CD68 in foamy histiocytes in a diffuse cytoplasmic staining pattern. (C) The histiocytes are negative for CD1a. (D) Positive immunostaining for BRAF V600E in foamy histiocytes. H&E, hematoxylin and eosin Table S1. BRAF inhibitors related adverse events Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.