Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study

Jean Donadieu 1 Islam Amine Larabi 2 Mathilde Tardieu 3 Johannes Visser 4 Caroline Hutter 5 Elena Sieni 6 Nabil Kabbara 7 Mohamed Barkaoui 8 Jean Miron 9 François Chalard 10 Paul Milne 11 Julien Haroche 12 Fleur Cohen 13 Zofia Hélias-Rodzewicz 14 Nicolas Simon 15 Mathilde Jehanne 16 Alexandra Kolenova 17 Anne Pagnier 18 Nathalie Aladjidi 19 Pascale Schneider 20 Genevieve Plat 21 Anne Lutun 22 Anne Sonntagbauer 23 Thomas Lehrnbecher 23 Alina Ferster 24 Viktoria Efremova 25 Martina Ahlmann 26 Laurence Blanc 27 James Nicholson 11 Anne Lambilliote 28 Houda Boudiaf 29 Andrej Lissat 30 Karel Svojgr 31 Fanette Bernard 32 Sarah Elitzur 33 Michal Golan 34 Dmitriy Evseev 35 Michael Maschan 35 Ahmed Idbaih 36, 37 Olga Slater 38 Milen Minkov 39 Valérie Taly 40 Matthew Collin 41 Jean-Claude Alvarez 42 Jean-François Emile 14 Sébastien Héritier 43
1 Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau]
2 AP-HP Hôpital Raymond Poincaré [Garches]
3 CHU - Centre Hospitalier Universitaire [Grenoble]
4 CUH - Cambridge University Hospitals - NHS
5 Medical University of Vienna
6 Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence
7 Departments of Hematology
8 GEH - Groupe d'Etude des Histiocytoses
9 Service d'Hémato-oncologie Pédiatrique
10 Service de Radiologie [CHU Trousseau]
11 Newcastle University [Newcastle]
12 Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares[CHU Pitié Salpêtrière]
13 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
14 Laboratoire épidémiologie et oncogénèse des tumeurs digestives
15 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
16 Centre Hospitalier Universitaire Félix-Guyon [Saint-Denis, La Réunion, France]
17 Comenius University Children's Hospital Limbova 1 [Bratislava, Slovakia]
18 Service Immuno Hémato-Onco Pédiatrique
19 Service d'Hémato-oncologie Pédiatrique
20 Service de pédiatrie médicale et médecine de l'adolescent [Rouen]
21 CHU Toulouse [Toulouse]
22 CHU Amiens-Picardie - Centre hospitalier universitaire d'Amiens
23 Universitätsklinikum Frankfurt
24 Hôpital Universitaire des Enfants - Reine Fabiola, Université Libre de Bruxelles
25 University Hospital [Minsk, Belarus]
26 Universitätsklinikum Münster Klinik für Kinder [Münster, Germany]
27 CHU Poitiers - Centre hospitalier universitaire de Poitiers
28 Hôpital Jeanne de Flandre [Lille]
29 Hôpital Mustapha [Mustapha, Algeria]
30 Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin
31 University Hospital Motol [Prague, Czech Republic]
32 HUG - Hôpitaux Universitaires de Genève
33 Schneider Children’s Medical Center of Israel [Petah Tikva]
34 The Edmond and Lily Safra Children's Hospital [Tel-Hahsomer, Israel]
35 Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia]
36 Sorbonne Université - Département de neurologie 2 - Mazarin
37 Centre Hospitalier Universitaire La Pitié-Salpêtrière-Charles Foix [Paris]
38 GOSH - Great Ormond Street Hospital for Children [London]
39 Sant'Anna Children's Hospital
40 MEPPOT - U1147 - Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique
41 Institute of Cellular Medicine [Newcastle]
42 Service de Pharmacologie Toxicologie [Garches]
43 SU FM - Sorbonne Université - Faculté de Médecine
Abstract : PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
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Submitted on : Friday, September 27, 2019 - 5:01:54 PM
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UVSQ | CNRS | ICM | UNIV-PARIS5 | COMUE-NORMANDIE | UNIROUEN | SORBONNE-UNIVERSITE | UNIV-PARIS7 | USPC | UNIV-PARIS-SACLAY | SU-MEDECINE

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Jean Donadieu, Islam Amine Larabi, Mathilde Tardieu, Johannes Visser, Caroline Hutter, et al.. Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. Journal of Clinical Oncology, American Society of Clinical Oncology, In press, pp.JCO.19.00456. ⟨10.1200/JCO.19.00456⟩. ⟨inserm-02299433⟩

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