Purpose
This study aimed to conduct a comprehensive genetic analysis of patients with Langerhans cell histiocytosis (LCH), focusing on the frequency of MAPK pathway mutations, detailed mutation profiles of MAPK pathway genes, and their correlation with clinical features and prognosis in Korean LCH patients.
Materials and Methods
We performed targeted next-generation sequencing, capable of capturing exons from 382 cancer-related genes, on genomic DNA extracted from formaldehyde-fixed and paraffin-embedded samples of 45 pathologically confirmed LCH patients.
Results
The majority of patients (91.1%) exhibited single-system disease, with bone being the most common location (84.4%). Initial treatments varied, and no patients died during a median follow-up of 6.8 years. Our genetic assays revealed that all patients had MAPK pathway alterations, including BRAF mutations in 51.2%, MAP2K1 mutations in 42.2%, RAF1 mutations in 4.4%, and a KRAS mutation in 2.2%. These mutations were mutually exclusive. Detailed mutation profiles indicated that among the BRAF mutations, there were 18 point mutations and 5 in-frame deletions, while most MAP2K1 mutations were in-frame deletions, with only one missense mutation. We detected previously unreported variations of point mutations in BRAF, MAP2K1, KRAS, and the first instance of a RAF1-KLC1 fusion in LCH. MAP2K1 mutations occurred more frequently in older patients, whereas BRAF V600 mutations were commonly associated with unifocal bone disease. Genetic mutations did not correlate with high-risk features or event-free survival.
Conclusion
This study identified mutually exclusive MAPK pathway mutations in every LCH patient through comprehensive genetic analysis, highlighting the importance of inclusive testing in understanding the disease's genetics.
Erdheim-Chester disease (ECD), also known as non-Langerhans cell histiocytosis, is a multi-systemic disease with unclear pathogenesis. Based on a small number of case studies, pegylated interferon-α (PEG-IFN-α) has been used as the front-line treatment option. However, there are limited data regarding administration of ropegylated-interferon α-2b (ROPEG-IFN-α 2b) for ECD patients. Herein, we report two cases of severe ECD treated with two types of PEG-IFN-α. One patient with heart and skeleton involvement and BRAF V600E mutation was treated with weekly PEG-IFN-α 2a. Another patient with bone involvement and no BRAF V600E mutation was administered monthly ROPEG-IFN-α 2b. The two types of PEG-IFN-α showed excellent disease control, excellent survival outcomes, and manageable toxicities in ECD patients. These results suggest that ROPEG-IFN-α 2b could be used equivalently to PEG-IFN-α 2a for management of advanced ECD.
Citations
Citations to this article as recorded by
An Autopsied Case of Erdheim-Chester Disease with Severe Cardiovascular Involvement Atsushi Matsunashi, Wang Zhipeng, Akihiko Sugimoto, Masakazu Fujimoto, Akihiko Yoshizawa, Ryo Sakamoto, Michihiro Uyama, Kohei Ikezoe, Kiminobu Tanizawa, Tomohiro Handa, Toyohiro Hirai Internal Medicine.2025;[Epub] CrossRef
Recent advances in therapeutic strategies of Erdheim-Chester disease Rohit Doke, Rahul Lokhande, Kalyani Chande, Kuldeep Vinchurkar, Bhupendra G. Prajapati Naunyn-Schmiedeberg's Archives of Pharmacology.2025;[Epub] CrossRef
Purpose
We sought to investigate the effectiveness and safety of dabrafenib in children with BRAFV600E-mutated Langerhans cell histiocytosis (LCH).
Materials and Methods
A retrospective analysis was performed on 20 children with BRAFV600E-mutated LCH who were treated with dabrafenib.
Results
The median age at which the patients started taking dabrafenib was 2.3 years old (range, 0.6 to 6.5 years). The ratio of boys to girls was 2.3:1. The median follow-up time was 30.8 months (range, 18.9 to 43.6 months). There were 14 patients (70%) in the risk organ (RO)+ group and six patients (30%) in the RO– group. All patients were initially treated with traditional chemotherapy and then shifted to targeted therapy due to poor control of LCH or intolerance to chemotherapy. The overall objective response rate and the overall disease control rate were 65% and 75%, respectively. During treatment, circulating levels of cell-free BRAFV600E (cfBRAFV600E) became negative in 60% of the patients within a median period of 3.0 months (range, 1.0 to 9.0 months). Grade 2 or 3 adverse effects occurred in five patients.
Conclusion
Some children with BRAFV600E-mutated LCH may benefit from monotherapy with dabrafenib, especially high-risk patients with concomitant hemophagocytic lymphohistiocytosis and intolerance to chemotherapy. The safety of dabrafenib is notable. A prospective study with a larger sample size is required to determine the optimal dosage and treatment duration.
Citations
Citations to this article as recorded by
Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis Chan-Juan Wang, Lei Cui, Shuang-Shuang Li, Hong-Hao Ma, Dong Wang, Hong-Yun Lian, Yun-Ze Zhao, Li-Ping Zhang, Wei-Jing Li, Qing Zhang, Xiao-Xi Zhao, Ying Yang, Xiao-Tong Huang, Wei Liu, Yi-Zhuo Wang, Wan-Shui Wu, Tian-You Wang, Rui Zhang, Zhi-Gang Li Archives of Pathology & Laboratory Medicine.2025; 149(2): 175. CrossRef
Targeted therapy and immunotherapy for orbital and periorbital tumors: a major review Emmanuel Lee Boniao, Richard C. Allen, Gangadhara Sundar Orbit.2024; 43(5): 656. CrossRef
Treatment of children with refractory/relapse high risk langerhans cell histiocytosis with the combination of cytarabine, vindesine and prednisone Wenqian Wang, Jian Ge, Honghao Ma, Hongyun Lian, Lei Cui, Yunze Zhao, Zhigang Li, Tianyou Wang, Rui Zhang BMC Pediatrics.2024;[Epub] CrossRef
Vemurafenib combined with chemotherapy achieved sustained remission in pediatric LCH: a multi-center observational study Jiaying Lei, Wenxia Wang, Danna Lin, Chengguang Zhu, Wenguang Jia, Wenjun Weng, Xiaoshan Liu, Yuhan Ma, Zhixuan Wang, Lihua Yang, Xiangling He, Yunyan He, Yang LI Journal of Cancer Research and Clinical Oncology.2024;[Epub] CrossRef
Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis Xinshun Ge, Wenxin Ou, Ang Wei, Hongyun Lian, Honghao Ma, Lei Cui, Dong Wang, Liping Zhang, Xiaoman Wang, Lejian He, Rui Zhang, Tianyou Wang BMC Pediatrics.2024;[Epub] CrossRef
Refractory juvenile xanthogranuloma of the mastoid bone responsive to trametinib Isaac Hauk, Ignacio Gonzalez‐Gomes, Deepak Chellapandian, Jonathan Metts, Peter H. Shaw Pediatric Blood & Cancer.2024;[Epub] CrossRef
Advancements in the understanding and management of histiocytic neoplasms Kyung-Nam Koh, Su Hyun Yoon, Sung Han Kang, Hyery Kim, Ho Joon Im Blood Research.2024;[Epub] CrossRef
Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium Paul G. Kemps, F. J. Sherida H. Woei-A-Jin, Patrick Schöffski, Thomas Tousseyn, Isabelle Vanden Bempt, Friederike A. G. Meyer-Wentrup, Natasja Dors, Natasha K. A. van Eijkelenburg, Marijn A. Scheijde-Vermeulen, Ingrid M. Jazet, Maarten Limper, Margot Jak, Blood Neoplasia.2024; 1(3): 100023. CrossRef
The clinical impact of serum soluble CD25 levels in children with Langerhans cell histiocytosis Zi-Jing Zhao, Hong-Yun Lian, Wei-Jing Li, Qing Zhang, Hong-Hao Ma, Dong Wang, Yun-Ze Zhao, Ting Zhu, Hua-Lin Li, Xiao-Tong Huang, Tian-You Wang, Rui Zhang, Lei Cui, Zhi-Gang Li Jornal de Pediatria.2024;[Epub] CrossRef
Liver transplantation in a child with sclerosing cholangitis due to Langerhans cell histiocytosis: a case report Xue-Lian Wang, Chun-Xiao Fang, Min-Xia Chen, Hua-Mei Yang, Lan-Hui She, Yu Gong, Yi Xu, Wei-Qiang Xiao, Jin-Sheng Tian, Bin Ai, Li Huang, Xu-Fang Li Frontiers in Pediatrics.2024;[Epub] CrossRef
BRAF V600E gene mutation is present in primary intraosseous Rosai-Dorfman disease Lokman Cevik, Swati Satturwar, Dan Jones, Joel Mayerson, Steve Oghumu, O. Hans Iwenofu Human Pathology.2024; 154: 105702. CrossRef
Langerhans cell histiocytosis as a clonal disease of mononuclear phagocyte system Evgeniy F. Khynku, Maria K. Monaenkova, Olga B. Tamrazova, Alexey V. Taganov, Мarina А. Gureeva, Gayane E. Bagramova, Anton V. Molochkov Almanac of Clinical Medicine.2023; 50(7): 428. CrossRef
Lineage switching of the cellular distribution of BRAF
V600E in multisystem Langerhans cell histiocytosis Paul Milne, Simon Bomken, Olga Slater, Ashish Kumar, Adam Nelson, Somak Roy, Jessica Velazquez, Kshitij Mankad, James Nicholson, Dan Yeomanson, Richard Grundy, Ahmed Kamal, Anthony Penn, Jane Pears, Gerard Millen, Bruce Morland, James Hayden, Jason Lam, M Blood Advances.2023; 7(10): 2171. CrossRef
Treatment of Langerhans Cell Histiocytosis and Histiocytic Disorders: A Focus on MAPK Pathway Inhibitors Ashley V. Geerlinks, Oussama Abla Pediatric Drugs.2023; 25(4): 399. CrossRef
Dabrafenib, alone or in combination with trametinib, in BRAF V600–mutated pediatric Langerhans cell histiocytosis James A. Whitlock, Birgit Geoerger, Ira J. Dunkel, Michael Roughton, Jeea Choi, Lisa Osterloh, Mark Russo, Darren Hargrave Blood Advances.2023; 7(15): 3806. CrossRef
Therapiestrategien bei Kindern und Jugendlichen mit Langerhanszell
Histiozytosen Anke Elisabeth Barnbrock, Caroline Hutter, Konrad Bochennek, Milen Minkov, Thomas Lehrnbecher Klinische Pädiatrie.2023; 235(06): 342. CrossRef
Mutant PIK3CA is a targetable driver alteration in histiocytic neoplasms Benjamin H. Durham, Oshrat Hershkovitz-Rokah, Omar Abdel-Wahab, Mariko Yabe, Young Rock Chung, Gilad Itchaki, Maayan Ben-Sasson, Vered A. Asher-Guz, David Groshar, Seyram A. Doe-Tetteh, Tina Alano, David B. Solit, Ofer Shpilberg, Eli L. Diamond, Roei D. M Blood Advances.2023; 7(23): 7319. CrossRef
Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations Marie Bellouard, Jean Donadieu, Pauline Thiebot, Etienne Giroux Leprieur, Philippe Saiag, Isabelle Etting, Pamela Dugues, Emuri Abe, Jean-Claude Alvarez, Islam-Amine Larabi Pharmaceutics.2023; 16(1): 5. CrossRef
Langerhans cell histiocytosis: promises and caveats of targeted therapies in high-risk and CNS disease Oussama Abla Hematology.2023; 2023(1): 386. CrossRef
Characteristics and Treatment Outcomes of Pediatric Langerhans Cell Histiocytosis with Thymic Involvement Ja-Feng Yao, Dong Wang, Hong-Hao Ma, Hong-Yun Lian, Li Zhang, Tian-You Wang, Zhi-Gang Li, Jin Jiang, Lei Cui, Rui Zhang The Journal of Pediatrics.2022; 244: 194. CrossRef
Clinical features and treatment outcomes of pediatric Langerhans cell histiocytosis with macrophage activation syndrome-hemophagocytic lymphohistiocytosis Dong Wang, Xi-Hua Chen, Ang Wei, Chun-Ju Zhou, Xue Zhang, Hong-Hao Ma, Hong-Yun Lian, Li Zhang, Qing Zhang, Xiao-Tong Huang, Chan-Juan Wang, Ying Yang, Wei Liu, Tian-You Wang, Zhi-Gang Li, Lei Cui, Rui Zhang Orphanet Journal of Rare Diseases.2022;[Epub] CrossRef
Current perspectives on the role of liver transplantation for Langerhans cell histiocytosis: A narrative review Jagadeesh Menon, Ashwin Rammohan, Mukul Vij, Naresh Shanmugam, Mohamed Rela World Journal of Gastroenterology.2022; 28(30): 4044. CrossRef
Research Progress of BRAF V600E Gene Mutation in Papillary Thyroid Carcinoma 延泽 刘 Advances in Clinical Medicine.2022; 12(09): 8499. CrossRef
Recent advances in the understanding of the molecular pathogenesis and targeted therapy options in Langerhans cell histiocytosis Jin Kyung Suh, Sunghan Kang, Hyery Kim, Ho Joon Im, Kyung-Nam Koh BLOOD RESEARCH.2021; 56(S1): S65. CrossRef
Improvement in Pituitary Imaging After Targeted Therapy in Three Children with BRAF-Mutated Langerhans Cell Histiocytosis with Pituitary Involvement
Ying Yang, Dong Wang, Na Li, Honghao Ma, Hongyun Lian, Lei Cui, Qing Zhang, Xiaoxi Zhao, Liping Zhang, Yunze Zhao, Chanjuan Wang, Li Zhang, Tianyou Wang, Zhigang Li, Rui Zhang OncoTargets and Therapy.2020; Volume 13: 12357. CrossRef