Childhood Langerhans cell histiocytosis hematological involvement: severity associated with <i>BRAF</i> <i>V600E</i> loads
Abstract
Abstract Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin &lt;10 g/dL, platelets &lt;100 × 109/L, leukopenia (white blood cell count &lt;4 × 109/L), and/or neutrophils &lt;1.5 × 109/L. Among the 2313 patients aged &lt;18 years enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis, 1 year); median follow-up lasted 8.1 years. Bone marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis, or myelofibrosis but never confirm the diagnosis. Fifty-eight patients (17%) developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; &gt;7 g/dL and &gt;20 × 109/L, respectively) and severe HI (SHI; ≤7 g/dL and/or ≤20 × 109/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities, and outcomes (MHI and SHI 10-year survival rates, 98% and 73%, respectively). Since 1998, mortality first declined with combination cladribine-cytarabine therapy and then with MAPK inhibitors since 2014. Forty-one patients (12%) developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, because it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted therapy approaches would be better adapted for these patients, whereas MHI can be managed with classic therapies.
Article Details
Authors (44)
Julian Thalhammer
9Department of Pediatric Hematology, Jeanne de Flandre Hospital, CHRU de Lille, Lille, France, Lille, France
Éric Jeziorski
Perrine Marec-Bérard
1Institute of Hematology and Pediatric Oncology, Centre Leon-Berard, Lyon, France
Mohamed Aziz Barkaoui
4French Reference Center for Histiocytosis, Assistance Publique–Hôpitaux de Paris, Paris, Hôpital Trousseau, Paris, France
Anne Pagnier
5Department of Pediatric Hematology and Oncology, CHU de Grenoble, Grenoble, France
Pierre-Simon Rohrlich
Aurore Chevallier
4French Reference Center for Histiocytosis, Assistance Publique–Hôpitaux de Paris, Paris, Hôpital Trousseau, Paris, France
Liana Carausu
7Department of Pediatric Hematology and Oncology, CHU de Brest, Brest, France
Nathalie Aladjidi
17Pediatric Oncology Hematology Unit, CEREVANCE, Plurithématique CIC (CICP), Centre d'Investigation Clinique (CIC) 1401, INSERM, Bordeaux University Hospital, Bordeaux, France, Bordeaux, France
Charlotte Rigaud
9Department of Children and Adolescents Oncology, Gustave-Roussy Cancer, Paris-Saclay University, Villejuif, France
Amaury Leruste
10Pediatric Oncology Department, Institut Curie, Paris, France
Saba Azarnoush
Thomas Lauvray
12Department of Pediatric Hematology and Oncology, CHU de Limoges, Limoges, France
Solenne Le Louet
4French Reference Center for Histiocytosis, Assistance Publique–Hôpitaux de Paris, Paris, Hôpital Trousseau, Paris, France
Virginie Gandemer
4CHU Rennes, Rennes, France
Pauline Treguier
14Department of Pediatric Hematology and Oncology, CHU de Rouen, Rouen, France
Ludovic Mansuy
15Department of Pediatric Hematology and Oncology, CHU de Nancy, Nancy, France
Marlène Pasquet
Department of Pediatric Hematology and Immunology Child Hospital, University Hospital of Toulouse, Toulouse, France
Laura Olivier
11CHU Toulouse, Toulouse, France
Angélique Rome
17Department of Pediatric Hematology and Oncology, CHU de Marseille, Hôpital La Timone, Marseille, France
Paul Saultier
1APHM Hospital de la Timone, Marseille, France
Fiorentina Isfan
18Department of Pediatric Hematology and Oncology, CHU de Clermont-Ferrand, Clermont-Ferrand, France
Cécile Renard
2IHOPE, Lyon, France
Valérie Li Thiao Te
4Service d’Hématologie-Oncologie et Immunologie Pédiatrique, CHU Amiens Picardie, Amiens, France
Alexandra Salmon
20Department of Pediatric Hematology and Oncology, Centre Hospitalier Régional Universitaire (CHRU) de Strasbourg, Strasbourg, France
Laurence Blanc
21Department of Pediatric Hematology and Oncology, CHU de Poitiers, Poitiers, France
Wadih Abou Chahla
9Department of Pediatric Hematology, Jeanne de Flandre Hospital, CHRU de Lille, Lille, France, Lille, France
Anne Lambilliotte
2Department of Pediatric Hematology, Centre Hospitalo-Universitaire (CHU) de Lille, Lille, France
Jean-Louis Stephan
22Department of Pediatric Hematology and Oncology, CHU de Saint-Etienne, Saint-Etienne, France
Frederic Geissmann
Julien Lejeune
24Service d'Onco-Hématologie Pédiatrique, CHRU de Tours, Hôpital Clocheville, Tours, France
Coralie Mallebranche
25Immuno-Hemato-Oncology Unit, University of Angers, CHU Angers, Angers, France
Yves Reguerre
26Department of Pediatric Hematology and Oncology, CHU de Saint-Denis, Hôpital Félix-Guyon, Saint-Denis, La Réunion, France
Audrey Grain
8Service d’Hématologie-Oncologie-Immunologie Pédiatrique, CHU Nantes, Nantes, France
Caroline Thomas
Zofia Hélias-Rodzewicz
5Ambroise-Paré Hospital, Department of Pathological Anatomy, Boulogne-Billancourt, France
Despina Moshous
8Université Paris Cité, Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants Malades Hospital, Paris, France, Paris, France
Odile Fenneteau
4Service d’Hématologie Biologique, Hôpital Robert Debré, Groupes Hospitalo-Universitaires Assistance Publique–Hôpitaux de Paris Nord, Université Paris Cité, Paris, France
Aurore Coulomb-L’herminé
Hélène Lapillonne
3Hôpital Trousseau, Sorbonne Université, AP-HP, Département d'Hématologie Biologique, Paris, France
Geneviève de Saint-Basile
33Université Paris-Cité, INSERM Unité Mixte de Recherche 1163, Imagine Institute, Paris, France
Jean-François Emile
Sébastien Héritier
17Pediatric Oncology Hematology Unit, CEREVANCE, Plurithématique CIC (CICP), Centre d'Investigation Clinique (CIC) 1401, INSERM, Bordeaux University Hospital, Bordeaux, France, Bordeaux, France
Jean Donadieu