Long-term MAPK inhibition of childhood refractory-Langerhans cell histiocytosis: an observational study of 288 patients
Year: 2026
Type: article
Study design: Observational Study
Abstract: ABSTRACT: 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.
Source: Blood Advances
Authors: Jean Donadieu, Dmitry Evseev, Francesco Pegoraro, Elena Sieni, Olga Slater, Caroline Hutter, Itziar Astigarraga, Thomas Lehrnbecher, Cor van den Bos, Mathieu Simonin, Martina Ahlmann, Mohamed Barkaoui, Solenne Le Louet, Aurore Chevallier, François Chalard, Trung Nguyen, Suzanne Holzhauer, Karin Beutel, Henriette Haenicke, Gabriele Escherich, Susana Garcia-Obregon, Lorena Valero-Arrese, David Ruano, Mara Andrés Moreno, Dalila Habes, Florence Lacaille, Valérie McLin, Simon Bomken, Hugh Bishop, Anthony Penn, Leonie Naeije, Nabil Kabbara, Paul Milne, Zofia Hélias-Rodzewicz, Alexandra Kolenova, Cecile Renard, Perinne Marec Berard, Julian Thalhammer, Anne Pagnier, Alexandra Salmon, Nathalie Aladjidi, Laura Olivier, Paul Saultier, Laurence Blanc, Virginie Gandemer, Pascale Schneider, Laila Hessissen, Michal Golan, Sarah Elitzur, Myriam Ben Arush, Dana Ashkenazi Lustig, Rina Dvir, Anna Raciborska, Zofia Malas, Safiatou Diallo, Gabriel Levy, Viktoria Efremova, Monica Cheng Munthe-Kaas, Tatiana von Bahr Greenwood, Guido Felizzia, Jorge Braier, Houda Boudiaf, Ilhem Ben Fraj, Karel Svojgr, Zdenka Krenova, Fanette Bernard, Cecile Adam, Eva Karaoli, Ines Ackerl Kristensen, Christine Dahl, Irene Trambusti, Stefania Gaspari, Carmela De Fusco, Stefano Chiaravalli, Paola Corti, Alessandra Todesco, Vassilios Papadakis, Ines Luz, Vitor Costa, Daria Osipova, Evelina Lyudovskikh, Michael Maschan, Gleb Bronin, Evgueni Burcev, Ahmed Idbaih, Islam Amine Larabi, Marie Bellouard, Jean-Claude Alvarez, Olga Novosad, Matthew Collin, Jan Inge Henter, Jean-François Emile, Sébastien Héritier, Milen Minkov
Institutions: Hôpital Armand-Trousseau, Assistance Publique – Hôpitaux de Paris, Kepler Universitätsklinikum, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Meyer Children's Hospital, Great Ormond Street Hospital, St Anna Children's Hospital, Medical University of Vienna, University of the Basque Country, BioCruces Health research Institute, Hospital de Cruces, University Hospital Frankfurt, Princess Máxima Center, University of Münster, University Hospital Münster, Charité - Universitätsmedizin Berlin, Helios Kliniken, University Medical Center Hamburg-Eppendorf, Vall d'Hebron Hospital Universitari, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Hospital Universitari i Politècnic La Fe, Bicêtre Hospital, Hôpital Necker-Enfants Malades, University of Geneva, Great North Children's Hospital, Royal Aberdeen Children's Hospital, National Health Service, Saint Joseph University, Rafik Hariri University Hospital, Rafik Hariri University, Newcastle University, Université Paris-Saclay, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie, Institut d’Hématologie et d’Oncologie Pédiatrique, Hospices Civils de Lyon, Centre Hospitalier Universitaire de Lille, Centre Hospitalier Universitaire de Grenoble, Hôpitaux Universitaires de Strasbourg, Centre Hospitalier Universitaire de Bordeaux, Centre Hospitalier Universitaire de Toulouse, Hôpital de la Timone, Centre Hospitalier Universitaire de Poitiers, Centre Hospitalier Universitaire de Rennes, Centre Hospitalier Universitaire de Rouen, Centre Hospitalier Ibn Sina, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Tel Aviv University, Schneider Children's Medical Center, Rambam Health Care Campus, Tel Aviv Sourasky Medical Center, Instytut Matki i Dziecka, Université Libre de Bruxelles, Queen Fabiola Children's University Hospital, Cliniques Universitaires Saint-Luc, Belarusian Research Center For Pediatric Oncology and Hematology, Oslo University Hospital, Karolinska University Hospital, Karolinska Institutet, Garrahan Hospital, Faculté de médecine de Tunis, Tunis El Manar University, University Hospital in Motol, University Hospital Brno, University Hospital of Geneva, Centre Hospitalier Universitaire Vaudois, Archbishop Makarios III Hospital, Aarhus University Hospital, Rigshospitalet, Bambino Gesù Children's Hospital, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Padua, Children's Hospital Agia Sophia, Unidade Local de Saúde de Coimbra, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Institut du Cerveau, Centre de recherche en Epidémiologie et Santé des Populations, Hôpital Raymond-Poincaré, National Cancer Institute
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W7128712304