Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy

• DOI: 10.1111/bjh.19462
• Publication Date: 2024-04-13T05:15:16Z
• Authors: Joshua S. Friedman; Benjamin H. Durham; Anne S. Reiner; Mariko Yabe; Kseniya Petrova‐Drus; Ahmet Dogan; Melissa Pulitzer; Klaus J. Busam; Jasmine H. Francis; Raajit K. Rampal; Gary A. Ulaner; Ryan Reddy; Randy Yeh; Vaios Hatzoglou; Mario E. Lacouture; Veronica Rotemberg; Roei D. Mazor; Oshrat Hershkovit...; Ofer Shpilberg; Gaurav Goyal; Ronald S. Go; Jithma P. Abeykoon; Karen Rech; Diana Morlote; Shiraz Fidai; Vedavyas Gannamani; Maryam Zia; Omar Abdel‐Wahab; Katherine S. Pana...; Marc K. Rosenblum; Eli L. Diamond
• Keywords: Male; Adult; Proto-Oncogene Proteins B-raf; Erdheim-Chester Disease; 0303 health sciences; Adolescent; Middle Aged; Young Adult; Histiocytosis, Langerhans-Cell; 03 medical and health sciences; Child, Preschool; Mutation; Humans; Female; Molecular Targeted Therapy; Histiocytosis, Sinus; Child; Protein Kinase Inhibitors; Aged

SummaryHistiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai–Dorfman–Destombes disease (RDD) and Erdheim–Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy‐proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty‐seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non‐V600‐BRAF, RAF1 and a BICD2‐BRAF fusion. A repeated‐measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19–137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03–0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.