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