Real-world experience with targeted therapy in patients with histiocytic neoplasms in the Netherlands and in Belgium

1. Objective responses to BRAF/MEK inhibition were observed across histiocytic neoplasms and regardless of mutational profile

2. Limitations include toxicity, frequent need for prolonged treatment, and rare instances of neurodegeneration despite vemurafenib therapy

Histiocytic disorders are rare hematologic neoplasms characterized by a notable dependence on mitogen-activated protein kinase signaling. With conventional therapies, a substantial proportion of histiocytosis patients experiences disease progression. Targeted therapy is an emerging treatment option, with the capability to induce robust responses. Yet, the number of reported patients remains limited. Here, we describe 40 patients with histiocytic neoplasms who were treated with targeted therapy in 7 hospitals in the Netherlands and Belgium. The cohort comprised 6 (15%) children and 34 (85%) adults with diverse histiocytoses, including Langerhans cell histiocytosis (LCH; n=12), Erdheim-Chester disease (n=14), central nervous system xanthogranuloma (n=2), Rosai-Dorfman disease (n=3), histiocytic sarcoma (n=2), ALK-positive histiocytosis (n=1), and mixed/unclassifiable histiocytosis (n=6). Five patients were included in a clinical trial; 35/40 (88%) received BRAF/MEK inhibitors outside of trials. Among these 35 patients with available follow-up data, median time on targeted treatment was 1.9 years (range: 0.1 – 5.8 years). Complete or partial responses were observed in 25/27 (93%) patients treated for multisystemic and/or solid lesions and 2/8 (25%) patients treated for neurodegenerative LCH. Responses were generally durable, although 10 patients lost response after dose reduction or therapy interruption. Responses were recaptured in 9/10 cases. Two patients developed new or progressive neurodegenerative lesions: 1 during and 1 after vemurafenib therapy. At last follow-up, 8/35 (23%) patients had stopped targeted therapy because of toxicity – all of whom were adults. This study corroborates the favorable outcomes of BRAF/MEK inhibition in histiocytosis patients described previously. However, it also highlights limitations and calls for prospective studies.