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
(1)
,
François Chalard
(1)
,
Paul Milne
(9)
,
Julien Haroche
(10)
,
Fleur Cohen
(11)
,
Zofia Hélias-Rodzewicz
(12)
,
Nicolas Simon
(13)
,
Mathilde Jehanne
(14)
,
Alexandra Kolenova
(15)
,
Anne Pagnier
(16)
,
Nathalie Aladjidi
(17)
,
Pascale Schneider
(18)
,
Genevieve Plat
(19)
,
Anne Lutun
(20)
,
Anne Sonntagbauer
(21)
,
Thomas Lehrnbecher
(21)
,
Alina Ferster
(22)
,
Viktoria Efremova
(23)
,
Martina Ahlmann
(24)
,
Laurence Blanc
(25)
,
James Nicholson
(9)
,
Anne Lambilliote
(26)
,
Houda Boudiaf
(27)
,
Andrej Lissat
(28)
,
Karel Svojgr
(29)
,
Fanette Bernard
(30)
,
Sarah Elitzur
(31)
,
Michal Golan
(32)
,
Dmitriy Evseev
(33)
,
Michael Maschan
(33)
,
Ahmed Idbaih
(10, 10)
,
Olga Slater
(34)
,
Milen Minkov
(35)
,
Valérie Taly
(36)
,
Matthew Collin
(37)
,
Jean-Claude Alvarez
(38)
,
Jean-François Emile
(12)
,
Sébastien Héritier
(39)
1
CHU Trousseau [APHP]
2 Hôpital Raymond Poincaré [AP-HP]
3 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
4 CUH - Cambridge University Hospitals - NHS
5 Medizinische Universität Wien = 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 Newcastle University [Newcastle]
10 CHU Pitié-Salpêtrière [AP-HP]
11 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
12 BECCOH - Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie
13 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
14 Centre Hospitalier Universitaire Félix-Guyon [Saint-Denis, La Réunion, France]
15 Comenius University in Bratislava
16 Service Immuno Hémato-Onco Pédiatrique
17 Service d'Hémato-oncologie Pédiatrique
18 Service de pédiatrie médicale et médecine de l'adolescent [Rouen]
19 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
20 CHU Amiens-Picardie
21 Universitätsklinikum Frankfurt
22 HUDERF - Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique]
23 University Hospital [Minsk, Belarus]
24 Universitätsklinikum Münster Klinik für Kinder [Münster, Germany]
25 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
26 Hôpital Jeanne de Flandre [Lille]
27 Hôpital Mustapha [Mustapha, Algeria]
28 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
29 University Hospital Motol [Prague, Czech Republic]
30 HUG - Hôpitaux Universitaires de Genève
31 Schneider Children’s Medical Center of Israel [Petah Tikva]
32 The Edmond and Lily Safra Children's Hospital [Tel-Hahsomer, Israel]
33 Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia]
34 GOSH - Great Ormond Street Hospital for Children [London]
35 Sant'Anna Children's Hospital
36 MEPPOT - U1147 - Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique
37 Institute of Cellular Medicine [Newcastle]
38 Service de Pharmacologie Toxicologie [Garches]
39 SU FM - Sorbonne Université - Faculté de Médecine
2 Hôpital Raymond Poincaré [AP-HP]
3 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
4 CUH - Cambridge University Hospitals - NHS
5 Medizinische Universität Wien = 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 Newcastle University [Newcastle]
10 CHU Pitié-Salpêtrière [AP-HP]
11 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
12 BECCOH - Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie
13 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
14 Centre Hospitalier Universitaire Félix-Guyon [Saint-Denis, La Réunion, France]
15 Comenius University in Bratislava
16 Service Immuno Hémato-Onco Pédiatrique
17 Service d'Hémato-oncologie Pédiatrique
18 Service de pédiatrie médicale et médecine de l'adolescent [Rouen]
19 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
20 CHU Amiens-Picardie
21 Universitätsklinikum Frankfurt
22 HUDERF - Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique]
23 University Hospital [Minsk, Belarus]
24 Universitätsklinikum Münster Klinik für Kinder [Münster, Germany]
25 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
26 Hôpital Jeanne de Flandre [Lille]
27 Hôpital Mustapha [Mustapha, Algeria]
28 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
29 University Hospital Motol [Prague, Czech Republic]
30 HUG - Hôpitaux Universitaires de Genève
31 Schneider Children’s Medical Center of Israel [Petah Tikva]
32 The Edmond and Lily Safra Children's Hospital [Tel-Hahsomer, Israel]
33 Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia]
34 GOSH - Great Ormond Street Hospital for Children [London]
35 Sant'Anna Children's Hospital
36 MEPPOT - U1147 - Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique
37 Institute of Cellular Medicine [Newcastle]
38 Service de Pharmacologie Toxicologie [Garches]
39 SU FM - Sorbonne Université - Faculté de Médecine
Elena Sieni
- Fonction : Auteur
- PersonId : 904052
Fleur Cohen
- Fonction : Auteur
- PersonId : 965083
Alina Ferster
- Fonction : Auteur
- PersonId : 760019
- ORCID : 0000-0002-9920-8359
Ahmed Idbaih
- Fonction : Auteur
- PersonId : 760123
- ORCID : 0000-0001-5290-1204
- IdRef : 114953139
Valérie Taly
- Fonction : Auteur
- PersonId : 177600
- IdHAL : valerie-taly
- ORCID : 0000-0002-3116-8602
- IdRef : 161486983
Matthew Collin
- Fonction : Auteur
- PersonId : 785302
- ORCID : 0000-0001-6585-9586
Jean-François Emile
- Fonction : Auteur
- PersonId : 757060
- ORCID : 0000-0002-6073-4466
- IdRef : 105749788
Résumé
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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