scholarly journals Failure of salvage vemurafenib therapy for refractory multisystem Langerhans cell histiocytosis with BRAF-V600E mutation

2021 ◽  
Author(s):  
Xue Tang ◽  
Zhi Wan ◽  
Xia Guo ◽  
Ju Guo
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Cost Effective ◽  
Salvage Treatment ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Myeloid Differentiation ◽  
Case Presentation ◽  
First Case ◽  
Steroid Regimen

Abstract Background Langerhans cell histiocytosis (LCH) has been defined as a disorder driven by misguided myeloid differentiation, with up to 50% of cases harboring the BRAF-V600E mutation. Salvage treatment with LCH refractory to vinblastine and steroid regimen is intractable. Vemurafenib is safe and effective in children with refractory BRAF-V600E-positive LCH, but the disease always reactivates with the withdrawal of vemurafenib. Case presentation: Here, we report the first case of BRAF-V600E positive LCH resistant to vemurafenib therapy but effectively salvaged by cytarabine-based chemotherapy. Conclusions Our case report shows that vemurafenib monotherapy might not be effective for every BRAF-V600E-positive refractory LCH, and cytarabine-based chemotherapy might still be a cost-effective therapeutic alternative. Keywords: Langerhans cell histiocytosis, BRAF-V600E mutation, Vemurafenib, Chemotherapy

scholarly journals Vemurafenib provides a rapid and robust clinical response in paediatric Langerhans cell histiocytosis with the BRAF V600E mutation but does not eliminate low-level minimal residual disease based on ddPCR using cell-free circulating DNA

2020 ◽  
Author(s):  
Dmitry Evseev ◽  
Irina Kalinina ◽  
Elena Raykina ◽  
Daria Osipova ◽  
Zalina Abashidze ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Residual Disease ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Circulating Dna ◽  
Neutropenic Sepsis ◽  
Day Range ◽  
Droplet Pcr ◽  
Free Circulating Dna

Background Langerhans cell histiocytosis (LCH) involves abnormal proliferation of Langerhans cells (LC), which is typically driven by the BRAF V600E mutation. High-risk LCH has a poor prognosis. Procedure Fifteen children (5 girls, 10 boys) with BRAF V600E+ LCH received vemurafenib (initial dose median 40 mg/kg/day, range: 11–51.6 mg/kg/day) between March 2016 and February 2020. All patients had previous received LCH-directed chemotherapy. The median age at LCH onset was 2 months (range: 1–28 months) and the median age at the start of vemurafenib treatment was 22 months (range: 13–62 months). The median disease activity score (DAS) at the start of vemurafenib treatment was 12 points (range: 2–22 points). Results The median duration of vemurafenib therapy was 29 months (range: 2.4–45 months). All patients responded to treatment, with median DAS values of 4 points (range: 0–14 points) at week 4 and 1 point (range: 0–3 points) at week 26. Toxicities included skin/hair changes (93%) and non-significant QT prolongation (73%). Two patients died, including 1 patient who experienced hepatic failure after NSAID overdose and 1 patient who developed neutropenic sepsis. Electively stopping vemurafenib treatment resulted in relapse in 5 patients, and complete cessation was only possible for 1 patient. Digital droplet PCR for BRAF V600E using cell-free circulating DNA revealed that 7 patients had mutation statuses that fluctuated over time. Conclusion Our study confirms that vemurafenib treatment is safe and effective for young children with BRAF V600E+ multisystem LCH. However, treatment using vemurafenib does not completely eliminate the disease.

BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis

2019 ◽  
Vol 22 (5) ◽  
pp. 449-455 ◽  
Author(s):  
Erdener Ozer ◽  
Akin Sevinc ◽  
Dilek Ince ◽  
Resmiye Yuzuguldu ◽  
Nur Olgun
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Erk Pathway ◽  
Disease Relapse ◽  
Multisystem Disease ◽  
Mutational Status

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.

scholarly journals ddPCR Analysis Reveals BRAF V600E Mutations Are Infrequent in Isolated Pituitary Langerhans Cell Histiocytosis Patients

2020 ◽  
Vol 79 (12) ◽  
pp. 1313-1319
Author(s):  
Anandani Nellan ◽  
Avery Bodlak ◽  
David M Mirsky ◽  
Jean Mulcahy Levy ◽  
Timothy P Garrington ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Pediatric Patients ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Pituitary Stalk ◽  
Molecular Alteration ◽  
Polymerase Chain ◽  
Myeloid Neoplasia ◽  
Pituitary Stalk Thickening

Abstract Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a highly variable clinical presentation affecting people of all ages. Mutations in BRAF V600E are the most identifiable molecular alteration in LCH although its incidence in pediatric patients with isolated pituitary stalk involvement is not well described. Pediatric patients with LCH and isolated pituitary stalk involvement typically present with central diabetes insipidus. Diagnosis requires a transcranial biopsy which often yields scant tissue. We sought to determine the prevalence of BRAF V600E mutations in patients with isolated pituitary stalk LCH using digital droplet polymerase chain reaction because this method requires minimal tumor DNA. We identified 8 patients with isolated pituitary stalk thickening who underwent a biopsy at Children’s Hospital Colorado from January 2001 to December 2019, as well as 6 patients with systemic LCH diagnosed by biopsy in the same period as a comparison. Only one out of the 8 patients with isolated thickened pituitary stalk was found to have a detectable BRAF V600E mutation. Five out of the 6 patients with systemic LCH had a detectable BRAF V600E mutation. In our series, BRAF V600E mutations are rare in pediatric patients with LCH and isolated pituitary stalk involvement.

High Prevalence of BRAF V600E Mutations in Langerhans Cell Histiocytosis of Head and Neck in Chinese Patients

2019 ◽  
Vol 27 (8) ◽  
pp. 836-843
Author(s):  
Xiaoxiao Liu ◽  
Ye Zhang ◽  
Chuan-Xiang Zhou
Keyword(s):  
Head And Neck ◽  
Langerhans Cells ◽  
Langerhans Cell Histiocytosis ◽  
Neck Region ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Chinese Patients ◽  
Clonal Proliferation ◽  
High Prevalence

Langerhans cell histiocytosis (LCH) is characterized by clonal proliferation of Langerhans cells and has been classified as a hematolymphoid tumor. BRAF V600E mutation was found to be frequent in LCH; however, it has also been reported that Asia patients with LCH tend to show a lower rate of BRAF V600E mutation. In this study, we found LCH from the head and neck region often involved bone especially the posterior of the mandible and presented a high prevalence of BRAF V600E mutation in Chinese patients. Our findings also showed immunohistochemical detection correlated very well to DNA sequencing of BRAF alterations, which may be useful in the diagnosis of LCH, especially in cases with a low proportion of Langerhans cells, and BRAF inhibitors might be a treatment option for patients with LCH harboring BRAF V600E mutation.

scholarly journals Multisystemic Pediatric Langerhans cell histiocytosis: a comprehensive clinico-pathological and BRAF V600E mutation study at autopsy

2020 ◽  
Vol 10 (2) ◽  
Author(s):  
Gargi Kapatia ◽  
Prateek Bhatia ◽  
Minu Singh ◽  
Richa Jain ◽  
Deepak Bansal ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e
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