Long-term MAPK inhibition of childhood refractory-Langerhans cell histiocytosis: an observational study on 288 patients

We evaluated long-term outcomes of 288 children with refractory-Langerhans cell histiocytosis (R-LCH) from 26 countries prescribed off-label mitogen-activated protein kinase inhibitors (MAPKis) according to clinical indications. MAPKi indications were: 148 R-risk-organ-positive (R-RO+), 67 R-RO-negative (R-RO-), 13 lung destruction (lung), 9 sclerosing cholangitis (SC), 49 neurodegeneration (ND) and 2 diabetes insipidus (DI). 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 were mostly prescribed as monotherapies: 184 vemurafenib, 115 dabrafenib, 3 encorafenib, 42 cobimetinib, 45 trametinib and/or 1 binimetinib; followed 51 times by various chemotherapies or hematopoietic stem-cell transplantation, or combined anti-BRAF-anti-MEK 28 times. 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%); 7 others were 1 cardiomyopathy and 6 retinitis. Five developed MAPKi-unrelated tumors. Nine 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, while 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.

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Journal
Blood Advances
Published
2026-02-12
DOI
https://doi.org/10.1182/bloodadvances.2025018651
Primary Topic
Histiocytic Disorders and Treatments
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article
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article

Long-term MAPK inhibition of childhood refractory-Langerhans cell histiocytosis: an observational study on 288 patients

Zdenka Křenová, A. Pagnier, Vassilios Papadakis, Caroline Hutter et al.
Blood Advances
Histiocytic Disorders and Treatments
article

Long-term MAPK inhibition of childhood refractory-Langerhans cell histiocytosis: an observational study on 288 patients

Zdenka Křenová, A. Pagnier, Vassilios Papadakis, Caroline Hutter, Marie Bellouard, Gabriel Levy, M Ahlmann, François Chalard, Nabil Kabbara, Evaggelia Karaoli, E. I. Lyudovskikh, Henriette Haenicke, Matthew Collin, D. A. Evseev, Cécile Adam, Inês Loureiro Luz, Laurence Blanc, Susanne Holzhauer, D. S. Osipova, Stefania Gaspari, Mathieu Simonin, Ilhem Ben Fraj, Mara M. Andres, Itziar Astigarraga, Jean‐Claude Alvarez, Trung Nguyen, Houda Boudiaf, Paul Saultier, Rina Dvir, Z Malas, Stefano Chiaravalli, Paul Milne, Pascale Schneider, Olga Slater, Irene Trambusti, Sébastien Heritier, Tatiana von Bahr Greenwood, G. Bronin, Alexandra Kolenová, Michal Golan, Viktoria Efremova, Olga Novosad, Sarah Elitzur, Jorge Braier, Florence Lacaille, Leonie Naeije, Perrine Marec-Berard, Paola Corti, Ines Ackerl Kristensen, Virginie Gandemer, Alexandra Salmon, Myriam Ben Arush, J Emile, Valrie A. McLin, Anthony Penn, Hugh Bishop, Laura Olivier, Lorena Valero-Arrese, Dana Ashkenazi Lustig, Elena Sieni, Islam Amine Larabi, Dalila Habes, M. Maschan, Thomas Lehrnbecher, Karel Švojgr, Laila Hessissen, Susana García-Obregón, Simon Bomken, Evgueni Burcev, Cor van den Bos, Vitor Costa, Jan-Inge Henter, Karin Beutel, Milen Minkov, Gabriele Escherich, Guido Andres Felizzia, Francesco Pegoraro, Christine Dahl, Alessandra Todesco, Safiatou Diallo, Nathalie Aladjidi, Ahmed Idbaih, Carmela De Fusco, David Ruano, Solenne Le Louet, Monica Cheng Munthe-Kaas, Anna Raciborska, Aurore Chevallier, Mohamed Barkaoui, Jean Donadieu, Zofia Hélias-Rodzewicz, Fanette Bernard
article en

Abstract

We evaluated long-term outcomes of 288 children with refractory-Langerhans cell histiocytosis (R-LCH) from 26 countries prescribed off-label mitogen-activated protein kinase inhibitors (MAPKis) according to clinical indications. MAPKi indications were: 148 R-risk-organ-positive (R-RO+), 67 R-RO-negative (R-RO-), 13 lung destruction (lung), 9 sclerosing cholangitis (SC), 49 neurodegeneration (ND) and 2 diabetes insipidus (DI). 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 were mostly prescribed as monotherapies: 184 vemurafenib, 115 dabrafenib, 3 encorafenib, 42 cobimetinib, 45 trametinib and/or 1 binimetinib; followed 51 times by various chemotherapies or hematopoietic stem-cell transplantation, or combined anti-BRAF-anti-MEK 28 times. 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%); 7 others were 1 cardiomyopathy and 6 retinitis. Five developed MAPKi-unrelated tumors. Nine 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, while 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.

Blood Advances
Tunis University (TN), Goethe University Frankfurt (DE), Hebron University (PS), Oslo University Hospital (NO), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Cliniques Universitaires Saint-Luc (BE), University of Padua (IT), Université de Bordeaux (FR), Inserm (FR), University of the Basque Country (ES), Charles University (CZ), Université Paris-Saclay (FR), Tel Aviv Sourasky Medical Center (IL), Garrahan Hospital (AR), Rafik Hariri University Hospital (LB), Great Ormond Street Hospital (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Grenoble (FR), Rambam Health Care Campus (IL), Eppendorf (Germany) (DE), Hospitais da Universidade de Coimbra (PT), Aarhus University Hospital (DK), Rigshospitalet (DK), Karolinska Institutet (SE), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), Institut Necker Enfants Malades (FR), Hôpital Armand-Trousseau (FR), Institut d’Hématologie et d’Oncologie Pédiatrique (FR), München Klinik Schwabing (DE), Assistance Publique – Hôpitaux de Paris (FR), Hospices Civils de Lyon (FR), University Hospital Brno (CZ), University Hospital Münster (DE), Centre de recherche en Epidémiologie et Santé des Populations (FR), Bordeaux Population Health (FR), University Hospital of Geneva (CH), Queen Fabiola Children's University Hospital (BE), Schneider Children's Medical Center (IL), Russian Children's Clinical Hospital (RU), Azienda Ospedaliera San Gerardo (IT), Royal Aberdeen Children's Hospital (GB), IPO Porto (PT), Centre Hospitalier Universitaire de Poitiers (FR), Hospital Infantil Universitario Niño Jesús (ES), CUF Porto Hospital (PT), Meyer Children's Hospital (IT), Rappaport Family Institute for Research in the Medical Sciences (IL), 9th City Clinical Hospital (BY), Kepler Universitätsklinikum (AT), München Klinik (DE), Pitié-Salpêtrière Hospital (FR), Leitat Technological Center (ES), Bambino Gesù Children's Hospital (IT), National Cancer Institute (UA), St Anna Children's Hospital (AT), Princess Máxima Center (NL), Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology (RU), Vall d'Hebron Hospital Universitari (ES), Centre Hospitalier Ibn Sina (MA), Hôpital Ambroise-Paré (FR), Mother and Child Foundation (GB), National Cancer Institute (MY), Hôpital Raymond-Poincaré (FR), Délégation Provence et Corse (FR), Hospital de Cruces (ES), Hôpital Purpan (FR), Archbishop Makarios III Hospital (CY), Edmond and Lily Safra Children's Hospital (IL), Centre Hospitalier Universitaire de Rouen (FR), Centro Hospitalar do Porto (PT), Hôpital Mustapha Pacha (DZ), Helios Hospital Berlin-Buch (DE), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Royal Manchester Children's Hospital (GB), Iaso Children’s Hospital (GR), Tashkent Pediatric Medical Institute (UZ), Bicêtre Hospital (FR), Haifa Medical Center (IL), St. Anna Children's Cancer Research Institute, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (FR), University College London (GB), Université de Rennes (FR), Université de Rouen Normandie (FR), Tunis El Manar University (TN), Université de Strasbourg (FR), Comenius University Bratislava (SK), Charité - Universitätsmedizin Berlin (DE), Newcastle University (GB), Université Grenoble Alpes (FR), University of Lausanne (CH)
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