Clinical and positron emission tomography responses to long-term high-dose interferon-α treatment among patients with Erdheim-Chester disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare multi-systemic form of histiocytosis. Treatment with BRAF inhibitors has markedly improved outcomes of ECD; however, this targeted therapy is expensive (estimated annual cost is $50,000). Since estimated annual cost of interferon-α (IFN-α) is only approximately $1600 in China, we retrospectively evaluated the long-term therapeutic efficacy of IFN-α and the value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as an assessment method among 32 ECD patients who received high dose IFN-α therapy at Peking Union Medical College Hospital. RESULTS: The median age at diagnosis was 48 years (range, 6-66 years). The median duration of treatment was 18.5 months (range, 1-51 months). The overall clinical response rates were 80.0%, including 33.3% complete response, 36.7% partial response and 10.0% stable disease. Thirty-one patients underwent a total of 81 scans by FDG-PET. Seventeen patients had serial FDG-PET results, nine patients had experienced a partial metabolic response at the last follow-up. The median reduction of ratios between the most active target lesion standardized uptake value (SUV) and liver SUV from baseline to last FDG-PET scan was 61.4% (range, 8.8-86.6%). Eight of thirteen patients who experienced continuous clinical improvement during follow-up had at least one target lesion SUV increased by FDG-PET which decreased in subsequent scans without changing treatment strategy. The estimated 3-year progression-free survival (PFS) and overall survival (OS) were 64.1 and 84.5%, respectively. Central nervous system (CNS) involvement was the only predictor for poor PFS and OS. CONCLUSIONS: High-dose IFN-α treatment is a cost-effective option, especially for patients without CNS involvement. Single target lesion SUV elevation according to FDG-PET do not accurately demonstrate disease progression, but serial FDG-PET imaging effectively discriminate treatment response.

Arterial involvement in Erdheim-Chester disease: A retrospective cohort study.

Erdheim-Chester disease (ECD) is a rare histiocytosis of the "L" (Langerhans) group with multisystem involvement that can affect the large and medium-sized arteries mimicking vasculitis. Aortic involvement is common but the frequency and outcome of aortic branch vessel abnormalities are less well described.Patients with ECD were retrospectively identified. Images containing information of arterial involvement within 6 months of diagnosis were considered baseline and compared to last follow-up studies. Two physicians independently reviewed the studies to evaluate for presence of abnormalities attributable to ECD. Age and sex-adjusted logistic regression models were used to examine associations between patient characteristics and vessel involvement at baseline.Among a cohort of 64 patients with ECD, 63 had baseline imaging of vascular structures. ECD involvement of at least 1 segment of the aorta was observed in 56%. Abnormalities were also observed in aortic arch branches (26%), visceral branch arteries (40%), iliofemoral arteries (31%), coronary (5%), and pulmonary (3%) arteries. Perinephric fibrosis was strongly associated with the identification of abnormalities in the thoracic aorta (OR 4.92 [1.54, 15.75]; P = .007), abdominal aorta (OR 7.57 [2.28, 25.07]; P = .001) and visceral branch arteries (OR 6.05 [1.52, 24.03]; P = .01) but not pelvic/lower extremity arteries. Complete normalization of arterial abnormalities at follow-up was only observed in 9% or less of arterial segments involved at baseline.Aortic and aortic branch vessel abnormalities are frequently observed in patients with ECD and are often asymptomatic. Partial and/or complete resolution of arterial findings is uncommon.

Prognostic factors of Erdheim-Chester disease: a nationwide survey in Japan.

Erdheim-Chester disease is a rare histiocytosis with insufficient clinical data. To clarify the clinical features and prognostic factors of Erdheim-Chester disease, we conducted a nationwide survey to collect the detailed data of 44 patients with Erdheim-Chester disease in Japan. The median age of onset of the participants was 51 (range: 23-76) years, and the median number of involved organs per patient was 4 (range: 1-11). The existence of central nervous system disease was correlated with older age (P=0.033), the presence of cardiovascular lesions (P=0.015), and an increased number of involved organs (P=0.0042). The median survival from the onset was 10.4 years, and >3.0 mg/dL C-reactive protein level at onset was associated with worse outcome (median survival, 14.6 vs. 7.4 years; P=0.0016). In a multivariate analysis, age >60 years (hazard ratio, 25.9; 95% confidence interval, 2.82-237; P=0.0040) and the presence of digestive organ involvement (hazard ratio, 4.74; 95% confidence interval, 1.05-21.4; P=0.043) were correlated with worse survival. Fourteen patients had available histological samples of Erdheim- Chester disease lesions. BRAFV600E mutation was detected in 11 patients (78%) by Sanger sequencing. A correlation between BRAF mutation status and clinical factors was not observed. Our study revealed that age and digestive organ involvement influence the outcome of Erdheim-Chester disease patients, and an inflammatory marker, such as C-reactive protein, might reflect the activity of this inflammatory myeloid neoplasm.

Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study.

IMPORTANCE: The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study. OBJECTIVE: To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study. DESIGN, SETTING, AND PARTICIPANTS: The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600-mutant ECD or LCH were enrolled in an "other solid tumor" cohort of the VE-BASKET study, and they were enrolled in the present study. INTERVENTIONS: Patients received vemurafenib, 960 mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety. RESULTS: A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51-74 years). The confirmed ORR was 61.5% (95% CI, 40.6%-79.8%) in the overall cohort and 54.5% (95% CI, 32.2%-75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86% (95% CI, 72%-100%), and 2-year OS was 96% (95% CI, 87%-100%). All 15 patients evaluated by FDG-PET/CT achieved a metabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma. CONCLUSIONS AND RELEVANCE: In this study, vemurafenib had prolonged efficacy in patients with BRAF V600-mutant ECD and LCH and warrants consideration as a new standard of care for these patients.

[Erdheim-Chester disease]. / Maladie d'Erdheim-Chester.

Erdheim-Chester disease is a rare and orphan disease. Despite having been overlooked previously, numerous new cases have been diagnosed more recently. The number of Erdheim-Chester disease cases reported has increased substantially: more than 300 new cases have been published in the past 10 years. This situation is mainly a result of the generally better awareness among pathologists, radiologists, and clinicians of various aspects of this rare disease. The field has been particularly active in the last few years, with evidence of the efficacy of interferon-α, the description of a systemic pro-inflammatory cytokine signature, and most recently, reports of the dramatic efficacy of BRAF inhibition in severe, BRAF(V600E) mutation-associated cases of Erdheim-Chester disease. Also, BRAF mutations have been found in more than half of the patients with Erdheim-Chester disease who were tested. Detailed elucidation of the pathogenesis of the disease is likely to lead to the development of better targeted and more effective therapies.

[Erdheim-Chester disease: study of 12 cases]. / Enfermedad de Erdheim-Chester: estudio de 12 casos.

BACKGROUND AND OBJECTIVE: Erdheim-Chester disease (EC) is a rare form of non-Langerhans' cell histiocytosis. It is characterized by the xanthomatous infiltration of tissues with foamy CD68+/CD1a- histiocytes. We report a series of 12 patients diagnosed with EC. PATIENTS AND METHODS: We reviewed the clinical, pathological and therapeutic aspects of 12 cases diagnosed with EC at 7 tertiary teaching hospitals in Spain. Patients were included if tissue infiltration by histiocytes CD68+/CD1a- could be demonstrated in an appropriate clinical setting. RESULTS: Twelve patients (7 male) were included. Median follow-up was 36 months (IQR: 20-84). The median age at the time of clinical onset and pathological diagnosis was 49 (IQR: 28-61) and 56 years (IQR: 37-62), respectively. In 6 cases multiples biopsies were performed (skin, muscle, testicular) previous to diagnosis, which was confirmed in 3 cases after a carefully review of pathological tissues. Neurological involvement was independently associated with mortality (P<.05). Characteristic long bone osteosclerosis was detected in 9 patients. CONCLUSION: EC is a multisystemic and heterogeneous clinicopathological condition. A high index of suspicion and fluent communication between clinicians and pathologists is necessary to achieve a correct diagnosis.

Unusual manifestation of Erdheim-Chester disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare multisystem non-Langerhans cell histiocytosis that is characterized histologically by xanthogranulomatous infiltrates and radiologically by symmetrical sclerosis of long bones. The xanthomatous process is characterized by prominent foamy histiocytes staining positive for CD68, occasionally for PS100 and negative for S100 and CD1a. Gastroenterological involvement is exceedingly rare. CASE PRESENTATION: This case report describes the case of a 69-year-old man who presented otherwise well to the gastroenterology department with unspecific abdominal symptoms, nausea, vomiting and weight loss. ECD involving the gastrointestinal tract was confirmed clinically, radiologically and histologically. CONCLUSION: Gastroenterological manifestation of ECD is rare but should be considered in the differential diagnosis in patients presenting with evidence of multi-organ disease and typical radiological features of Erdheim-Chester disease elsewhere.

CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis, with noncodified therapeutic management and high mortality. No treatment has yet been shown to improve survival in these patients. We conducted a multicenter prospective observational cohort study to assess whether extraskeletal manifestations and interferon-α treatment would influence survival in a large cohort of ECD patients. To achieve this goal, we thoroughly analyzed the clinical presentation of 53 patients with biopsy-proven ECD, and we performed a survival analysis using Cox proportional hazard model. Fifty-three patients (39 men and 14 women) with biopsy-proven ECD were followed up between November 1981 and November 2010. Forty-six patients (87%) received interferon-α and/or PEGylated interferon-α. Multivariate survival analysis using Cox proportional hazard model revealed that central nervous system involvement was an independent predictor of death (hazard ratio = 2.51; 95% confidence interval, 1.28-5.52; P = .006) in our cohort. Conversely, treatment with interferon-α was identified as an independent predictor of survival (hazard ratio = 0.32; 95% confidence interval, 0.14-0.70; P = .006). Although definitive confirmation would require a randomized controlled trial, these results suggest that interferon-α improves survival in ECD patients. This may be seen as a significant advance, as it is the first time a treatment is shown to improve survival in this multisystemic disease with high mortality.

Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin. It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by spumous ("foamy") histiocytes. As of this writing, 178 cases have been reported. ECD is characterized by heterogeneous systemic manifestations. Bone pain is the most frequent symptom. About half of all patients have extraskeletal manifestations. Cardiovascular manifestations of ECD remain underestimated. We report 6 new cases of ECD associated with periaortic fibrosis. In 4 of these cases, the whole aorta had a "coated" aspect. A literature review revealed 66 cases of ECD with cardiovascular involvement. We therefore analyzed 72 ECD patients with cardiovascular involvement: 40 (55.6%) had periaortic "fibrosis," 32 (44.4%) had pericardial involvement, and 22 (30.6%) had myocardial involvement. Six had a right atrial tumor. Symptomatic valvular heart disease (3 aortic and 3 mitral regurgitations) was found in 6 patients. Nineteen patients (26.4%) had heart failure, leading to death in 8 cases. Six patients had renovascular hypertension related to perirenal artery stenosis. Data concerning follow-up were available for 58 (80.6%) patients. Of these, 35 (60.3%) patients died, confirming the severe prognosis of ECD. Cardiovascular complications were responsible for the death of 11 of the 35 patients (31.4%).