EFFICACY OF VEMURAFENIB COMBINED WITH CYTARABINE AND 2-CHLORO-2′-DEOXYADENOSINE AS FIRST-LINE THERAPY IN CHILDREN WITH MULTISYSTEM LANGERHANS CELL HISTIOCYTOSIS

Vollständiger Abstract

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Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder of childhood, driven by pathological activation of the MAPK signaling pathway. The multisystem form with riskorgan involvement (RO+) carries the worst prognosis. BRAF inhibitors show high initial efficacy, but monotherapy is associated with a high reactivation rate after discontinuation, underscoring the need to optimize first-line therapy. Objective: To evaluate the efficacy and tolerability of a combined protocol of vemurafenib with reduced-dose cytarabine (ARA-C) and 2-chloro-2′-deoxyadenosine (2-CdA) as first-line therapy in children with BRAF-positive multisystem LCH. Materials and Methods: A retrospective two-center observational study. Children with BRAF+ multisystem LCH (RO+ and RO–) treated with the protocol as first-line therapy in 2022–2025 were included. The protocol comprised 4 courses of vemurafenib (20 mg/kg/day) alternating with blocks of ARA-C (200 mg/m2/day) and 2-CdA (6 mg/m2/day) at reduced doses; total duration 196 days. Disease activity was assessed with the Disease Activity Score (DAS); complete response (non-active disease, NAD) was defined as 0 points. Event-free survival (EFS) was estimated by the Kaplan–Meier method; the Wilcoxon signed-rank test was used to compare DAS before and after treatment. Results: Twenty patients were enrolled (RO+, n=16; RO–, n=4). In the RO+ group, median age was 9 (1–22) months and median DAS 13 (5–16). NAD was achieved in all 20 (100%) patients, most by the first assessment point. Five-year EFS in the RO+ group was 75%. Reactivation occurred in 3/16 RO+ and 1/4 RO– patients; re-initiation of targeted therapy was effective in all cases. No grade III–IV toxicity (CTCAE v5.0) or disease progression was observed. A decline in BRAF-V600E allelic burden was seen in all 8 evaluated patients. Conclusion: First-line vemurafenib combined with reduced-dose ARA-C/2-CdA achieves NAD in all patients with low organ toxicity and may be considered an alternative to existing first-line regimens in children with multisystem LCH, both RO+ and RO–.