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Lookup NU author(s): Dr Simon BomkenORCiD, Dr Paul Milne, Professor Matthew CollinORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2026 American Society of Hematology. We evaluated long-term outcomes of 288 children with refractory-Langerhans cell histiocytosis (R-LCH) from 26 countries, who were prescribed off-label MAPK inhibitors (MAPKis) according to clinical indications. MAPKi indications included 148 R-risk-organ–positive (R-RO+), 67 R-risk-organ–negative (R-RO–), 13 lung destruction (lung), 9 sclerosing cholangitis (SC), 49 neurodegeneration (ND), and 2 diabetes insipidus (DI) cases. Median ages at diagnosis and MAPKi onset were 1.3 and 2.3 years, respectively, with median follow-up of 3.7 years (1166 person-years). Agents mostly prescribed as monotherapies were 184 prescriptions of vemurafenib, 115 of dabrafenib, 3 of encorafenib, 42 of cobimetinib, 45 of trametinib, and/or 1 prescription of binimetinib; followed 51 times by various chemotherapies or hematopoietic stem-cell transplantation, or 28 times by combined anti-BRAF–anti-MEK. Short-term responses (<8 weeks) ranged from 98% (R-RO+ and R-RO–), to 30% (lung) to none (ND, DI, and SC); although long-term lung and ND responses could be observed. Skin rash was the most frequent adverse event (∼55%), and 7 others included 1 case of cardiomyopathy and 6 of retinitis. Five developed MAPKi-unrelated tumors and 9 patients died. Five-year survival was 98%. After 113 patients with R-LCH discontinued MAPKi, 69 experienced disease reactivation. None of the various empirical maintenance therapies were able to prevent secondary reactivation. Among the 143 assessable patients without ND-LCH at MAPKi onset, 60 developed ND (45%, 5-year risk). MAPKis appeared to be safe and effective in children with R-RO+/RO–LCH, whereas other indications’ responses were less frequent or occurred later. Further studies are needed to find effective maintenance-therapy approaches, particularly to prevent frequently observed secondary ND.
Author(s): Donadieu J, Evseev D, Pegoraro F, Sieni E, Slater O, Hutter C, Astigarraga I, Lehrnbecher T, van den Bos C, Simonin M, Ahlmann M, Barkaoui M, Le Louet S, Chevallier A, Chalard F, Nguyen T, Holzhauer S, Beutel K, Haenicke H, Escherich G, Garcia-Obregon S, Valero-Arrese L, Ruano D, Moreno MA, Habes D, Lacaille F, McLin V, Bomken S, Bishop H, Penn A, Naeije L, Kabbara N, Milne P, Helias-Rodzewicz Z, Kolenova A, Renard C, Berard PM, Thalhammer J, Pagnier A, Salmon A, Aladjidi N, Olivier L, Saultier P, Blanc L, Gandemer V, Schneider P, Hessissen L, Golan M, Elitzur S, Ben Arush M, Lustig DA, Dvir R, Raciborska A, Malas Z, Diallo S, Levy G, Efremova V, Munthe-Kaas MC, von Bahr Greenwood T, Felizzia G, Braier J, Boudiaf H, Ben Fraj I, Svojgr K, Krenova Z, Bernard F, Adam C, Karaoli E, Kristensen IA, Dahl C, Trambusti I, Gaspari S, De Fusco C, Chiaravalli S, Corti P, Todesco A, Papadakis V, Luz I, Costa V, Osipova D, Lyudovskikh E, Maschan M, Bronin G, Burcev E, Idbaih A, Larabi IA, Bellouard M, Alvarez J-C, Novosad O, Collin M, Henter JI, Emile J-F, Heritier S, Minkov M
Publication type: Article
Publication status: Published
Journal: Blood Advances
Year: 2026
Volume: 10
Issue: 10
Pages: 3733-3743
Print publication date: 26/05/2026
Online publication date: 16/02/2026
Acceptance date: 14/01/2026
Date deposited: 01/06/2026
ISSN (print): 2473-9529
ISSN (electronic): 2473-9537
Publisher: American Society of Hematology
URL: https://doi.org/10.1182/bloodadvances.2025018651
DOI: 10.1182/bloodadvances.2025018651
Data Access Statement: The full-text version of this article contains a data supplement.
PubMed id: 41678955
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