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1. French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes

Author

Matthieu Groh, Julien Rohmer, Nicolas Etienne, Wadih Abou Chahla, Antoine Baudet, Aurélie Chan Hew Wai, Cécile Chenivesse, Irena Clisson Rusek, Vincent Cottin, Matthieu Decamp, Pascal De Groote, Fanny Delahousse, Nicolas Duployez, Stanislas Faguer, Frédéric Gottrand, Florent Huang, Thierry Leblanc, Antoine Magnan, Thierry Martin, Geoffrey Mortuaire, Antoine Néel, Luc Paris, Arnaud Petit, Julien Rossignol, Nicolas Schleinitz, Juliette Soret-Dulphy, Delphine Staumont-Salle, Benjamin Terrier, Louis Terriou, Jean-François Viallard, Guillaume Lefèvre, and Jean-Emmanuel Kahn

Subjects
Hypereosinophilia, Hypereosinophilic syndromes, Recommendation, Management, Medicine
Abstract

Abstract Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients’ association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Published
2023
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2. Germline bi-allelic SH2B3/LNK alteration predisposes to a neonatal juvenile myelomonocytic leukemia-like disorder

Author

Chloé Arfeuille, Yoann Vial, Margaux Cadenet, Aurélie Caye-Eude, Odile Fenneteau, Quentin Neven, Adeline A Bonnard, Simone Pizzi, Giovanna Carpentieri, Yline Capri, Katia Girardi, Lucia Pedace, Marina Macchiaiolo, Kamel Boudhar, Monia ben Khaled, Wadih Abou Chahla, Anne Lutun, Mony Fahd, Séverine Drunat, Elisabetta Flex, Jean-Hugues Dalle, Marion Strullu, Franco Locatelli, Marco Tartaglia, and Hélène Cavé

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options.

Published
2023
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3. Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden

Author

Thomas Pincez, Helder Fernandes, Thierry Leblanc, Gérard Michel, Vincent Barlogis, Yves Bertrand, Bénédicte Neven, Wadih Abou Chahla, Marlène Pasquet, Corinne Guitton, Aude Marie-Cardine, Isabelle Pellier, Corinne Armari-Alla, Joy Benadiba, Pascale Blouin, Eric Jeziorski, Frédéric Millot, Catherine Paillard, Caroline Thomas, Nathalie Cheikh, Sophie Bayart, Fanny Fouyssac, Christophe Piguet, Marianna Deparis, Claire Briandet, Eric Dore, Capucine Picard, Frédéric Rieux-Laucat, Judith Landman-Parker, Guy Leverger, and Nathalie Aladjidi

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IM). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS’CEREVANCE cohort. Median age at final follow-up was 18.5 years (range, 6.8–50.0 years) and the median follow-up period was 11.3 years (range, 5.1–38.0 years). At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM). A wide range of cIM occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IM. The number of cIM was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio 1.4, 95% Confidence Interval: 1.15–1.60, P=0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 years (range, 1.7–31.5 years), and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, long-term outcomes of pES showed remission of cytopenias but frequent IM linked to high second-line treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.

Published
2021
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4. Germline pathogenic variants in transcription factors predisposing to pediatric acute myeloid leukemia: results from the French ELAM02 trial

Author

Laurène Fenwarth, Nicolas Duployez, Alice Marceau-Renaut, Wadih Abou Chahla, Stéphane Ducassou, Virginie Gandemer, Marlène Pasquet, Thierry Leblanc, Pascale Schneider, Carine Domenech, Paul Saultier, Guy Leverger, Hélène Lapillonne, Claude Preudhomme, and Arnaud Petit

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2020
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5. Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients

Author

Jean Donadieu, Marie Lamant, Claire Fieschi, Flore Sicre de Fontbrune, Aurélie Caye, Marie Ouachee, Blandine Beaupain, Jacinta Bustamante, Hélène A. Poirel, Bertrand Isidor, Eric Van Den Neste, Antoine Neel, Stanislas Nimubona, Fabienne Toutain, Vincent Barlogis, Nicolas Schleinitz, Thierry Leblanc, Pierre Rohrlich, Felipe Suarez, Dana Ranta, Wadih Abou Chahla, Bénédicte Bruno, Louis Terriou, Sylvie Francois, Bruno Lioure, Guido Ahle, Françoise Bachelerie, Claude Preudhomme, Eric Delabesse, Hélène Cave, Christine Bellanné-Chantelot, and Marlène Pasquet

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.

Published
2018
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7. Impact of age at diagnosis, sex, and immunopathological manifestations in 886 patients with pediatric chronic immune thrombocytopenia

Author

Thomas Pincez, Helder Fernandes, Marlène Pasquet, Wadih Abou Chahla, Jérome Granel, Sébastien Héritier, Mony Fahd, Stéphane Ducassou, Caroline Thomas, Nathalie Garnier, Vincent Barlogis, Eric Jeziorski, Sophie Bayart, Pascal Chastagner, Nathalie Cheikh, Corinne Guitton, Catherine Paillard, Julien Lejeune, Frédéric Millot, Valérie Li‐Thiao Te, Coralie Mallebranche, Isabelle Pellier, Bénédicte Neven, Corinne Armari‐Alla, Liana Carausu, Christophe Piguet, Joy Benadiba, Claire Pluchart, Jean‐Louis Stephan, Marianna Deparis, Claire Briandet, Eric Doré, Aude Marie‐Cardine, Thierry Leblanc, Guy Leverger, and Nathalie Aladjidi

Subjects
Hematology
Published
2023

8. Determinants of long-term outcomes of splenectomy in pediatric autoimmune cytopenias

Author

Thomas Pincez, Nathalie Aladjidi, Sébastien Héritier, Nathalie Garnier, Mony Fahd, Wadih Abou Chahla, Helder Fernandes, Claire Dichamp, Stéphane Ducassou, Marlène Pasquet, Sophie Bayart, Despina Moshous, Nathalie Cheikh, Catherine Paillard, Dominique Plantaz, Eric Jeziorski, Caroline Thomas, Corinne Guitton, Marianna Deparis, Aude Marie Cardine, Jean-Louis Stephan, Isabelle Pellier, Eric Doré, Joy Benadiba, Claire Pluchart, Claire Briandet, Vincent Barlogis, Guy Leverger, and Thierry Leblanc

Subjects
Cohort Studies, Immunology, Splenectomy, Humans, Anemia, Hemolytic, Autoimmune, Cell Biology, Hematology, Child, Thrombocytopenia, Biochemistry
Abstract

Splenectomy is effective in ∼70% to 80% of pediatric chronic immune thrombocytopenia (cITP) cases, and few data exist about it in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). Because of the irreversibility of the procedure and the lack of predictions regarding long-term outcomes, the decision to undertake splenectomy is difficult in children. We report here factors associated with splenectomy outcomes from the OBS’CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP, n = 120; AIHA, n = 19; ES, n = 22) with a median (minimum-maximum) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.21-0.72, P = .003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR, 0.22; 95% CI, 0.12-0.39; P = 2.8 × 10−7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes.

Published
2022

9. Consensus survey on the management of children with chemotherapy-induced febrile neutropenia and at low risk of severe infection

Author

François Dubos, Aude Givone, Jean Duval-Destin, Mathilde Delebarre, Wadih Abou-Chahla, and Cyril Lervat

Abstract

Purpose: To identify national consensus criteria for the management of children with chemotherapy-induced febrile neutropenia (FN) and for evidence-based step-down treatment approaches for patients classified as having a low risk of severe infection. Methods: In August 2018, a five-section, 38-item survey was e-mailed to all pediatric hematology and oncology units in France. The five sections contained statements on possible consensus criteria for (i) the definition of FN, (ii) the initial management of children with FN, (iii) the conditions required for initiating step-down therapy in low-risk patients, (iv) the management strategy for low-risk patients, and (v) antibiotic treatment on discharge. Consensus was defined as 75% of “somewhat agree” + “strongly agree” answers. Results: Sixty-five physicians, all specialists in pediatric onco-hematology, from 18 centers completed the survey questionnaire (participation rate: 58%). A consensus was reached on 22 of the 38 statements, including the definition of FN, the criteria for step-down therapy in children at low risk of severe infection, and the initial care of patients with FN. There was no consensus on the type and duration of antibiotic therapy on discharge for patients at low risk of severe infection. Conclusion: A consensus has been reached on the criteria for initiating evidence-based step-down treatment of children with FN and a low risk of severe infection. The lack of consensus on the step-down antimicrobial regimen means that the post-discharge antibiotic treatment can be defined according to local preferences.

Published
2023

10. Germline Mutations of Telomere-Related Genes are a Major Risk Factor for Liver Disease: A Multicentric Transversal Study

Author

Sabrina Sidali, Raphaël Borie, Flore Sicre de Fontbrune, Kinan El Husseini, Pierre-Emmanuel Rautou, Elodie Lainey, Odile Goria, Bruno Crestani, Jacques Cadranel, Vincent Cottin, Vincent Bunel, Jérôme Dumortier, Emmanuel Jacquemin, Noémi Reboux, Sandrine Hirschi, Arnaud Bourdin, Magdalena Meszaros, Sébastien Dharancy, Sophie Hilaire, Vincent Mallet, Martine Reynaud-Gaubert, Louis Terriou, Frédéric Gottrand, Wadih Abou Chahla, Jean-Emmanuel Kahn, Paul Carrier, Faouzi Saliba, Laura Rubbia-Brandt, John-David Aubert, Laure Elkrief, Victor de Ledinghen, Armand Abergel, Olivier Tournilhac, Pauline Houssel, Stéphane Jouneau, Ludivine Wemeau, Anne Bergeron, Thierry Leblanc, Isabelle Ollivier-Hourmand, Eric Nguyen-Khac, Hélène Morisse-Pradier, Ibrahima Ba, Catherine Boileau, Françoise Roulot-Thoraval, Valérie Vilgrain, Christophe Bureau, Hilario Nunes, Jean-Marc Naccache, François Durand, Claire Francoz, Dominique Roulot, Dominique-Charles Valla, Valérie Paradis, Caroline Kannengiesser, and Aurélie Plessier

Published
2023

11. Invasive Fungal Infections in Immunocompromised Children: Novel Insight Following a National Study

Author

Laura Olivier-Gougenheim, Wadih Abou-Chahla, Pascale Schneider, Damien Dupont, Sandrine Thouvenin-Doulet, Claire Desplantes, Stéphane Ducassou, Nathalie Cheikh, Claire Freycon, Benoit Brethon, Fanny Rialland, Claire Pluchart, Yves Bertrand, Alexandre Theron, Geneviève Plat, Audrey Contet, Carine Domenech, Virginie Gandemer, Catherine Paillard, Nicolas Rama, Maryline Poirée, Paul Saultier, Elodie Gouache, Guy Leverger, Jérémie Rouger-Gaudichon, Pascale Blouin, Isabelle Pellier, and Caroline Oudot

Subjects
Male, Fusariosis, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Hematopoietic stem cell transplantation, Aspergillosis, Immunocompromised Host, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Epidemiology, medicine, Humans, 030212 general & internal medicine, Child, Retrospective Studies, Acute leukemia, business.industry, Incidence, Mucormycosis, Hematopoietic Stem Cell Transplantation, Infant, Newborn, Infant, Retrospective cohort study, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Leukemia, Myeloid, Acute, Leukemia, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, France, business, Invasive Fungal Infections
Abstract

To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT).We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units.From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P.0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.

Published
2021

12. Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series

Author

Pierre-Simon Rohrlich, Souha Albinni, Wadih Abou-Chahla, Benedicte Neven, Jérôme Babinet, Christophe Marguet, Felipe Suarez, Olivier Hermine, Faustine Lhomme, Sébastien Héritier, Olivier Lortholary, Isabelle Durieu, Nizar Mahlaoui, Alain Fischer, Marie-Dominique Dumont, Stéphane Blanche, Despina Moshous, Denise Amiranoff, and Thierry Peyrard

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Duchenne muscular dystrophy, medicine.medical_treatment, Immunology, Disease, Hematopoietic stem cell transplantation, Granulomatous Disease, Chronic, Young Adult, Chronic granulomatous disease, Isoantibodies, Retinitis pigmentosa, Epidemiology, medicine, Humans, Immunology and Allergy, CYBB, Child, Retrospective Studies, business.industry, Infant, medicine.disease, Survival Analysis, Abetalipoproteinemia, Child, Preschool, NADPH Oxidase 2, Primary immunodeficiency, Female, France, business, Neuroacanthocytosis, Follow-Up Studies
Abstract

X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.

Published
2020

13. Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE-related neutropenia: a French Severe Chronic Neutropenia Registry study

Author

Aude Marie-Cardine, Flore Sicre de Fontbrune, Stéphane Blanche, Despina Moushous, Thierry Leblanc, Christine Bellanné-Chantelot, Fanny Rialland, Nathalie Aladjidi, Claire Freycon, Virginie Gandemer, Catherine Paillard, Blandine Beaupain, Marlène Pasquet, French Severe Chronic Neutropenia Registry, Marie-Gabrielle Vigue, Wadih Abou-Chahla, Christophe Piguet, Frédéric Millot, Martin Biosse-Duplan, Pacifique Lévy, Cecile Renard, Jean Donadieu, Gioacchino Andrea Rotulo, Geneviève Plat, Vincent Barlogis, Claire Fieschi, Therapeia Rehabilitation Center, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Registre des neutropénies chroniques [CHU Trousseau], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital des Enfants, CHU Toulouse [Toulouse], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, Assistance Publique - Hôpitaux de Marseille (APHM), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Rouen, Normandie Université (NU), CHU Strasbourg, CHU Bordeaux [Bordeaux], Hôpital Bretonneau, Amgen SAS, Chugai SA, Inserm, Association Sportive de Saint-Quentin–Fallavier, Société d’Hémato-Immunologie Pédiatrique, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Adult, medicine.medical_specialty, Neutropenia, Adolescent, severe congenital neutropenia, [SDV]Life Sciences [q-bio], Disease, medicine.disease_cause, 03 medical and health sciences, Cyclic neutropenia, Young Adult, 0302 clinical medicine, Recurrence, Internal medicine, medicine, Humans, Registries, Child, 030304 developmental biology, 0303 health sciences, ELANE-related neutropenia, business.industry, Elastase, Hematopoietic Stem Cell Transplantation, Genetic Variation, Infant, Hematology, Bacterial Infections, medicine.disease, opportunistic infections, 3. Good health, Transplantation, Pneumonia, Mycoses, Staphylococcus aureus, 030220 oncology & carcinogenesis, Cellulitis, France, business, Leukocyte Elastase, Follow-Up Studies
Abstract

International audience; Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease’s natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (3000/mm(3) ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.

Published
2021

14. An appraisal of the frequency and severity of noninfectious manifestations in primary immunodeficiencies: A study of a national retrospective cohort of 1375 patients over 10 years

Author

Mickaël Alligon, Nizar Mahlaoui, Virginie Courteille, Laurence Costes, Veronica Afonso, Philippe Randrianomenjanahary, Nathalie de Vergnes, Anja Ranohavimparany, Duy Vo, Inès Hafsa, Perrine Bach, Vincent Benoit, Nicolas Garcelon, Alain Fischer, Wadih Abou-Chahla, Daniel Adoue, Nathalie Aladjidi, Corinne Armari-Alla, Vincent Barlogis, Sophie Bayart, Yves Bertrand, Stéphane Blanche, Damien Bodet, Bernard Bonnotte, Raphaël Borie, Patrick Boutard, David Boutboul, Claire Briandet, Jean-Paul Brion, Jacques Brouard, Liana Carausu, Martin Castelle, Pascal Cathebras, Emilie Catherinot, Nathalie Cheikh, Morgane Cheminant, Sarah Cohen-Beaussant, Thibault Comont, Louis-Jean Couderc, Pierre Cougoul, Gérard Couillault, Lionel Crevon, Elisa Demonchy, Anne Deville, Catherine Devoldere, Eric Dore, Fabienne Dulieu, Isabelle Durieu, Natacha Entz-Werle, Claire Fieschi, Fanny Fouyssac, Pierre Frange, Vincent Gajdos, Lionel Galicier, Virginie Gandemer, Martine Gardembas, Catherine Gaud, Bernard Grosbois, Aurélien Guffroy, Corinne Guitton, Gaëlle Guillerm, Eric Hachulla, Mohamed Hamidou, Sophie Haro, Yves Hatchuel, Olivier Hermine, Cyrille Hoarau, Arnaud Hot, Sébastien Humbert, Arnaud Jaccard, Jean-Philippe Jais, Sarah Jannier, Serge Jacquot, Roland Jaussaud, Pierre-Yves Jeandel, Eric Jeziorski, Kamila Kebaili, Anne-Sophie Korganow, Olivier Lambotte, Fanny Lanternier, Claire Larroche, David Launay, Emmanuelle Le Moigne, Alain Le Quellec, Vincent Le Moing, Yvon Lebranchu, Marc Lecuit, Guillaume Lefèvre, Jean-Daniel Lelièvre, Richard Lemal, Valérie Li-Thiao-Te, Olivier Lortholary, Luminita Luca, Coralie Mallebranche, Marion Malphettes, Aude Marie-Cardine, Nicolas Martin-Silva, Agathe Masseau, Françoise Mazingue, Etienne Merlin, Gérard Michel, Frédéric Millot, Charline Miot, Béatrice Monlibert, Fabrice Monpoux, Despina Moshous, Luc Mouthon, Martine Münzer, Robert Navarro, Bénédicte Neven, Dalila Nouar, Raphaële Nove-Josserand, Eric Oksenhendler, Marie Ouachée-Chardin, Anne Pagnier, Marlène Pasquet, Isabelle Pellier, Yves Perel, Antoinette Perlat, Christophe Piguet, Dominique Plantaz, Sophie Rivière, Pascal Roblot, Pierre-Simon Rohrlich, Bruno Royer, Valéry Salle, Françoise Sarrot-Reynauld, Amélie Servettaz, Jean-Louis Stephan, Nicolas Schleinitz, Harry Sokol, Felipe Suarez, Laure Swiader, Sophie Taque, Caroline Thomas, Olivier Tournilhac, Caroline Thumerelle, Jean-Pierre Vannier, and Jean-François Viallard

Subjects
Inflammation, Neoplasms, Immunology, Hypersensitivity, Immunologic Deficiency Syndromes, Immunology and Allergy, Humans, Autoimmunity, Retrospective Studies
Abstract

Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

Published
2021

15. Pediatric-Onset Evans Syndrome Is Associated with Broad Immunopathological Manifestations, High Treatment Burden and Mortality in Long-Term Follow-up

Author

Eric Jeziorski, Frédéric Millot, Wadih Abou Chahla, Joy Benadiba, Corinne Armari-Alla, Nathalie Aladjidi, Thierry Leblanc, Helder Fernandes, Claire Briandet, Sophie Bayard, Fanny Fouyssac, Thomas Pincez, Christophe Piguet, Yves Bertrand, Marlène Pasquet, Caroline Thomas, Judith Landman-Parker, Isabelle Pellier, Bénédicte Neven, Pascale Blouin, Corinne Guitton, Vincent Barlogis, E. Dore, Catherine Paillard, Aude Marie-Cardine, Gérard Michel, Nathalie Cheikh, Mariana Deparis, and Guy Leverger

Subjects
Pediatrics, medicine.medical_specialty, Evans syndrome, Long term follow up, business.industry, Pediatric onset, Immunology, Treatment burden, Cell Biology, Hematology, medicine.disease, Biochemistry, medicine, business
Abstract

Introduction Pediatric-onset Evans syndrome (pES) is defined by the association between immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years and may be associated to various immunopathological manifestations (IMs). No comprehensive study of this rare disease exists, and its long-term outcomes are poorly described. Methods Patients from the nationwide French prospective OBS'CEREVANCE cohort with pES and more than 5 years of follow-up were included (excepted pES secondary to bone marrow transplantation or primary immunodeficiencies known at the inclusion). All patients, including those with less than 5 years of follow-up, were included in survival analyses. Multivariate Cox proportional hazards model was used to analyze factors associated with time-dependent variables. Results Of the 216 patients with pES in the cohort, 151 (88 males and 63 females) were included with a median (min-max) follow-up time after first cytopenia diagnosis of 11.3 (5.1-38) years. Median age at final follow-up was 18.5 (6.8-50.0) years. The proportion of patients achieving a sustained complete response (i.e. persisting until final follow-up) increased after cytopenia onset (Fig. 1A). ITP and AIHA were in complete remission in 40.5% and 54.5%, 74.1% and 62.3%, and 78.4% and 86% of patients at 5, 10, and 15 years, respectively. Clinical IMs (cIMs) developed in 100/151 patients (66%), before the first diagnosis of cytopenia in 21/100 cases. The number of cIMs increased over time (Fig. 1B). The proportions of patients with one and more than one cIM were 50% and 14%, 57% and 19%, and 81% and 44% at 5, 10, and 15 years after the first cytopenia diagnosis, respectively. A broad spectrum of cIMs were present, lymphoproliferation (n = 71), dermatological (n = 26), gastrointestinal/hepatic (n = 23), and pneumological manifestations (n = 16) being the most common. Three patients had a hematological malignancy. Biological IMs (bIMs) were diagnosed in 101/151 patients (67%) and also increased over time, with hypogammaglobulinemia (n = 54) being the most common. Autoimmune neutropenia developed in 43 patients (28.5%) and was independently associated with the number of cIMs (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.5-3.8; p = 0.0002). Severe or recurrent infections were present in 53 patients (35%). The number of second-line treatments received (i.e. other than steroids and immunoglobulins) increased over time without reaching a plateau (Fig. 1C). Half of the patients had received at least one, two, and three different treatments at 2.7, 10.5, and 14.7 years after the first cytopenia diagnosis, respectively. The number of cIMs was independently associated with the number of second-line treatments received (HR, 1.3; 95% CI, 1.08-1.6; p = 0.006). Systemic lupus erythematosus (SLE) was diagnosed in 11/151 patients (7.3%, 1/88 males and 10/63 females) and autoimmune lymphoproliferative syndrome (ALPS) in six (4.0%). Sixteen of the 151 patients followed for more than 5 years (10.6%) died, and seven died before the fifth year of follow-up (23 deaths in total). Survival at 5, 10, and 15 years after the first cytopenia was 97%, 92%, and 84%, respectively (Fig. 1D). Deaths occurred regularly throughout the follow-up period, at a median age of 18.0 (1.7-31.5) years. The most frequent cause of death was infections (n = 12, 52%). Four patients (18%) died of hemorrhage, all were less than 13 years old. The numbers of second-line treatments (HR, 1.3; 95% CI, 1.1-1.6; p = 0.004) and severe or recurrent infections (HR, 3.4; 95% CI, 1.2-9.7; p = 0.02) were independently associated with mortality after 5 years of follow-up. Overall, 20-year-old compared to 10-year-old patients more frequently showed a sustained complete response for AIHA (72% vs. 30%) and ITP (50% vs. 26%), but more frequently had cIMs (74% vs. 37%), bIMs (75% vs. 39%), and ongoing second-line treatments (88% vs. 47%; p < 0.001 for all comparisons). Conclusions Long-term outcomes of pES were associated to IMs and second-line treatment burden, not active cytopenia. The significant mortality rates, mostly among adolescents and young adults, were linked to drug-induced and/or constitutive immunodeficiencies. Few cases were associated with SLE or ALPS, which is consistent with a heterogeneous genetic background. These results highlight the importance of multidisciplinary care during the transition from childhood to adulthood. Figure 1 Disclosures No relevant conflicts of interest to declare.

Published
2020

16. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

Author

Helder Fernandes, Guy Leverger, Vincent Barlogis, Yves Bertrand, Mohammed Zarhrate, Corinne Pondarré, E. Dore, Nathalie Cheikh, Elodie Colomb Bottollier, Caroline Thomas, Eric Jeziorski, Frédéric Rieux-Laucat, Fabienne Mazerolles, Y Perel, Capucine Picard, Pascale Blouin, Cécile Fourrage, Nicolas Garcelon, Aude Magerus-Chatinet, Marlène Pasquet, Sylvain Hanein, Benedicte Neven, Dominique Plantaz, Nathalie Aladjidi, Fanny Fouyssac, Thierry Leblanc, Jérémie Rosain, Alain Fischer, Marie-Claude Stolzenberg, Stéphane Ducassou, Sidonie Jacques, Frédéric Millot, Jérôme Hadjadj, Wadih Abou Chahla, Isabelle Pellier, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Hospices Civils de Lyon, Departement de Neurologie (HCL), Service d'Immuno-Hémato-Oncologie Pédiatrique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Clermont-Ferrand, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Rieux-Laucat, Frédéric, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Collège de France - Chaire Médecine expérimentale (A. Fischer), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Hôpital des Enfants, Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École Pratique des Hautes Études (EPHE), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hôpital Arnaud de Villeneuve, École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Collège de France (CDF), and Collège de France (CdF)

Subjects
Adult, Male, Evans syndrome, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, Biochemistry, Genetic determinism, LRBA, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Humans, Medicine, Child, 030304 developmental biology, Genetic testing, Autoimmune disease, 0303 health sciences, Mutation, medicine.diagnostic_test, business.industry, Infant, Cell Biology, Hematology, medicine.disease, Thrombocytopenia, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Child, Preschool, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Anemia, Hemolytic, Autoimmune, Autoimmune hemolytic anemia, business
Abstract

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

Published
2019

17. Germline pathogenic variants in transcription factors predisposing to pediatric acute myeloid leukemia: results from the French ELAM02 trial

Author

Carine Domenech, Marlène Pasquet, Stéphane Ducassou, Arnaud Petit, Paul Saultier, Claude Preudhomme, Nicolas Duployez, Guy Leverger, Hélène Lapillonne, Alice Marceau-Renaut, Laurène Fenwarth, Thierry Leblanc, Pascale Schneider, Virginie Gandemer, Wadih Abou Chahla, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], CHU Toulouse [Toulouse], Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Rouen, Normandie Université (NU), Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
[SDV]Life Sciences [q-bio], Bioinformatics, Germline, 03 medical and health sciences, 0302 clinical medicine, Text mining, Medicine, Humans, Genetic Predisposition to Disease, Child, Letters to the Editor, Transcription factor, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Pediatric acute myeloid leukemia, Hematology, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, Germ Cells, 030220 oncology & carcinogenesis, Disease Susceptibility, business, Transcription Factors
Abstract

International audience

Published
2021

18. Prospective Evaluation of the First Option, Second-Line Therapy in Childhood Chronic Immune Thrombocytopenia: Splenectomy or Immunomodulation

Author

Rodolphe Thiébaut, Corinne Armari-Alla, Marlène Pasquet, Thierry Leblanc, Nathalie Aladjidi, Guy Leverger, Stéphane Ducassou, Wadih Abou Chahla, Hélène Savel, Corinne Guitton, Vincent Barlogis, Helder Fernandes, Isabelle Pellier, Gilles Vassal, Yves Bertrand, Caroline Thomas, Nathalie Cheikh, Salim Laghouati, Sophie Bayart, Djamel Kherfellah, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Unité de Soutien Méthodologique à la Recherche Clinique (USMR), CHU Bordeaux [Bordeaux], CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), Institut d’Hématologie et d’Oncologie Pédiatriques, Hôpital Robert Debré, CHU Lille, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Grenoble, Hôpital Bicêtre, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut Gustave Roussy (IGR), Université Paris-Saclay, Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, hydroxychloroquine, Adolescent, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Splenectomy, Azathioprine, Gastroenterology, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, rituximab, children, 030225 pediatrics, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Child, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Purpura, Thrombocytopenic, Idiopathic, azathioprine, business.industry, Autoimmune Cytopenia, Infant, Hydroxychloroquine, Immune thrombocytopenia, 3. Good health, Child, Preschool, Chronic Disease, Pediatrics, Perinatology and Child Health, Cohort, second-line treatment, Female, Rituximab, business, medicine.drug
Abstract

International audience; Objective: To describe 4 subgroups of pediatric patients treated with splenectomy, hydroxychloroquine, azathioprine, or rituximab as the first-option, second-line treatment for chronic immune thrombocytopenia.Study design: Selection of patients with chronic immune thrombocytopenia from the French national prospective cohort of pediatric autoimmune cytopenia OBS'CEREVANCE and VIGICAIRE study, treated by splenectomy, hydroxychloroquine, azathioprine, or rituximab as a first second-line treatment.Results: For 137 patients, treated between 1989 and 2016, the median follow-up after diagnosis and after treatment initiation was 8.5 (2.8-26.4) years and 4.7 (1.1-25.1) years, respectively. Median age at diagnosis and at initiation of treatment were 9 (0.7; 16) and 12 (2; 18.1) years, respectively without significant difference between subgroups. For the whole cohort, 24-month event-free survival was 62% (95% CI 55; 71). It was 85% (95% CI 77; 95) for the 56 patients treated with splenectomy, 60% (95% CI 44; 84) for the 23 patients treated with rituximab, 46% (95% CI 30; 71) for the 24 patients treated with azathioprine, and 37% (95% CI 24; 59) for the 34 patients treated with hydroxychloroquine (log-rank P < .0001). For the splenectomy subgroup, being older than 10 years at splenectomy tended to improve event-free survival (P = .05). Female teenagers with antinuclear antibody positivity benefited from hydroxychloroquine therapy.Conclusions: This national study, limiting pitfalls in the analysis of the effects of second-line therapies, showed that splenectomy remains the treatment associated with the better response at 24 months.

Published
2020

19. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

Author

Baoyu Chen, Susan Price, Moza Al Hassani, M. Cecilia Poli, Ivan K. Chinn, Zeynep H. Coban-Akdemir, Tram N. Cao, Sarah Cook, Sylvain Latour, Gehad ElGhazali, Geoffrey D.E. Cuvelier, Jason W. Caldwell, Sheng Yang, D. Eric Anderson, Jordan S. Orange, Douglas B. Kuhns, Lisa R. Forbes, Alexander Vargas-Hernández, Soma Jyonouchi, Nikita Raje, Aiman J. Faruqi, V. Koneti Rao, Michael J. Lenardo, Benjamin Fournier, Alexandre F. Carisey, Donna M. Muzny, Shalini N. Jhangiani, James R. Lupski, Morgan Similuk, Wadih Abou Chahla, Janis K. Burkhardt, Yanping Huang, Nawal Al Kaabi, William A. Comrie, Richard A. Gibbs, Margery G. Smelkinson, Emily M. Mace, Zain Al Yafei, Andrew J. Oler, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
CD4-Positive T-Lymphocytes, medicine.medical_treatment, T cell, [SDV]Life Sciences [q-bio], Mechanistic Target of Rapamycin Complex 2, Biology, Filamentous actin, mTORC2, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, Phosphorylation, Mechanistic target of rapamycin, Immunodeficiency, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Multidisciplinary, Immunologic Deficiency Syndromes, Membrane Proteins, medicine.disease, Actins, Lymphoproliferative Disorders, 3. Good health, Cell biology, Pedigree, Wiskott-Aldrich Syndrome Protein Family, Cytokine, medicine.anatomical_structure, biology.protein, Cytokines, ADP-Ribosylation Factor 1, 030217 neurology & neurosurgery
Abstract

An inherited disorder makes WAVEs The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies. Science , this issue p. 202

Published
2020

20. Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing

Author

Brigitte Bader-Meunier, Thibault Comont, Felipe Suarez, Alain Fischer, Vincent Barlogis, David Boutboul, Claire Fieschi, Guillaume Vogt, Marlène Pasquet, Frédéric Rieux-Laucat, Jérémie Rosain, Marine Gil, Lionel Galicier, Etienne Merlin, Cécile Fourrage, Christine Bole, Nicholas Renaud, Wadih Abou Chahla, Capucine Picard, Sylvain Hanein, Stéphane Blanche, Patrick Nitschké, Despina Moshous, Benedicte Neven, Isabelle André, Virginie Grandin, Alexandre Alcaïs, Sylvain Latour, Jean-Pierre de Villartay, Chantal Lagresle-Peyrou, Jean-Sebastien Diana, Eric Oksenhendler, Marion Malphettes, Samuel Chevalier, Elisabeth Hulier-Ammar, Olivier Hermine, Mathieu Fusaro, Jacinta Bustamante, Nathalie Lambert, Vivien Béziat, Geneviève de Saint Basile, Nizar Mahlaoui, Martin Castelle, Sven Kracker, Alain Lefevre-Utile, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
0301 basic medicine, Adult, Male, Adolescent, Primary Immunodeficiency Diseases, health care facilities, manpower, and services, [SDV]Life Sciences [q-bio], Immunology, education, MEDLINE, Immunoglobulins, Bioinformatics, DNA sequencing, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immunology and Allergy, Medicine, Guanine Nucleotide Exchange Factors, Humans, Child, health care economics and organizations, Aged, Primary (chemistry), business.industry, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Middle Aged, medicine.disease, 3. Good health, I-kappa B Kinase, 030104 developmental biology, Child, Preschool, Cohort, Mutation, Etiology, Primary immunodeficiency, Female, business, 030215 immunology
Abstract

This study aims to validate a targeted next-generation sequencing panel of 300 genes to diagnose a cohort of 129 patients with primary immunodeficiency with no prior molecular etiology.

Published
2020

21. Baseline dysmegakaryopoiesis in inherited thrombocytopenia/platelet disorder with predisposition to haematological malignancies

Author

Marc Fouassier, Nathalie Trillot, Claude Preudhomme, Véronique Tintiller, Coralie Derrieux, Elise Fournier, Céline Berthon, Nicolas Duployez, Camille Debord, Soraya Wuilleme, Valérie Soenen, Thomas Boyer, Louis Terriou, Camille Paris, Fanny Gonzales, Sophie Susen, Anne Lambilliotte, Pierre Boisseau, Wadih Abou Chahla, Hôpital Claude Huriez [Lille], CHU Lille, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandre [Lille], Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU de Lille), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Régional de Traitement des Hémophiles [CHU Nantes], DESSAIVRE, Louise, and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011)

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, business.industry, Platelet disorder, [SDV]Life Sciences [q-bio], MEDLINE, Infant, Hematology, Middle Aged, Gastroenterology, Thrombocytopenia, [SDV] Life Sciences [q-bio], Internal medicine, Hematologic Neoplasms, medicine, Humans, Female, Genetic Predisposition to Disease, Blood Platelet Disorders, Baseline (configuration management), business, ComputingMilieux_MISCELLANEOUS, Germ-Line Mutation
Abstract

International audience

Published
2020

22. Effectiveness of in-Line Filters to Completely Remove Particulate Contamination During a Pediatric Multidrug Infusion Protocol

Author

Maxime, Perez, Bertrand, Décaudin, Wadih, Abou Chahla, Brigitte, Nelken, Laurent, Storme, Morgane, Masse, Christine, Barthélémy, Gilles, Lebuffe, Pascal, Odou, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Jeanne de Flandre [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Environnement périnatal et croissance - EA 4489 (EPS), CHU Lille, Université de Lille, Environnement Périnatal et Santé - EA 4489, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], and Environnement périnatal et croissance - EA 4489 [EPS]

Subjects
[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Leukemia, lcsh:R, lcsh:Medicine, Article, Intensive Care Units, Pharmaceutical Preparations, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Humans, Drug Therapy, Combination, Particulate Matter, lcsh:Q, Particle Size, Child, Drug Contamination, Infusions, Intravenous, lcsh:Science, Filtration
Abstract

International audience; The large number of drugs administered simultaneously to neonates and children in hospital results in the formation of particles that are potentially infused. We have investigated the ability of IV in-line filters to eliminate particulate matter from multidrug infusion lines and so prevent contamination. The impact on particle occurrence of the internal volume of the IV line below the in-line filter was then evaluated. The multidrug therapy given to children was reproduced with and without in-line filtration. Three combinations with a filter were tested to vary the internal volume (V) between the filter and the catheter egress. The catheter was then connected to a dynamic particle count to evaluate the particulate matter potentially administered to children during infusion. The introduction of in-line filters led to a significant reduction in overall particulate matter, from 416,974 [208,479-880,229] to 7,551 [1,985-11,287] particles (p

Published
2018

23. Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia

Author

Nicolas Duployez, Yves Bertrand, Thomas Boyer, Alice Marceau-Renaut, Sandrine Geffroy, Pauline Peyrouze, Sophie Lejeune, Wadih Abou Chahla, Nathalie Grardel, Gérard Michel, Guillaume Letizia, Brigitte Nelken, and Claude Preudhomme

Subjects
Male, 0301 basic medicine, Heterozygote, Adolescent, Somatic cell, DNA Mutational Analysis, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Germline, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Germline mutation, hemic and lymphatic diseases, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Germ-Line Mutation, Mutation, Proto-Oncogene Proteins c-ets, Hematology, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Repressor Proteins, Transplantation, ETV6, 030104 developmental biology, Cancer research, 030215 immunology
Abstract

ETV6 is a target of recurrent aberrations in sporadic and familial acute lymphoblastic leukemia (ALL). Here, we report on a new pedigree with a germline ETV6 mutation in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. The index patient achieved durable complete remission without transplantation but had persistent moderate thrombocytopenia without bleeding tendency. To determine the prevalence of ETV6 alterations in HeH-ALL, we screened 81 unrelated subjects with HeH-ALL by single nucleotide polymorphism array and high-throughput sequencing for the ETV6 gene. Overall, ETV6 microdeletions and mutations were identified in 9% of cases, all of which were somatic and considered as secondary events. Apart from the index patient, no germline ETV6 aberration was identified. Finally, we reviewed the literature for ETV6 germline aberrations and predispositions to ALL.

Published
2017

24. Impact and Dynamics of TP53 Mutated Clones in Shwachman Diamond Syndrome in a Series of 80 Patients

Author

Eric Jeziorski, Yves Bertrand, Flore Sicre de Fontbrune, Virginie Gandemer, Blandine Beaupain, Frédéric Millot, Jean Donadieu, François Delhommeau, Jean-Alain Martignoles, Marie-Laure Couec, Claude Preudhomme, Laetitia Largeaud, Cecile Renard, Nathalie Aladjidi, Pierre-Simon Rohrlich, Wadih Abou Chahla, Claire Fieschi, Sophie Kaltenbach, Stéphane Blanche, Despina Moushous, Pierre Hirsch, Isabelle Meyts, Guy Leverger, Thomas Longval, Jean Louis Stephan, Vincent Barlogis, Aline Moignet Autrel, Fanny Fouyssac, Dalila Adjaoud, Marlène Pasquet, Olivier Tournilhac, Vahid Asnafi, Patrick Revy, Pascale Flandrin-Gresta, Christine Bellanné-Chantelot, Liana Carausu, Nawa Hachem, Thierry Leblanc, Hélène Lapillonne, Jean Soulier, and Mira El-Khoury

Subjects
Shwachman–Diamond syndrome, medicine.medical_specialty, Acute leukemia, business.industry, Immunology, Cell Biology, Hematology, SBDS, medicine.disease, Biochemistry, Transplantation, Germline mutation, Internal medicine, Cohort, medicine, Aplastic anemia, Prospective cohort study, business
Abstract

Introduction : Hematological complications (HC) as Aplastic anemia (AA) and myelodysplasia and acute leukemia (MDS/AL) are frequent and life threatening in patients with Shwachman Diamond Syndrome (SDS) with SBDS mutations. The therapy of such events is based on Hematopoetic stem cell transplantation (HSCT), which results remain quite poor, especially in case of malignancy. So far, it is difficult to anticipate to such HC and a lot is expected from the study of clonal evolution prior HC. Methods: A Targeted panel of 43 genes involved in MDS/AL (sensibility 1%) has been evaluated in 80 patients with SBDS mutation, representative of a nation based cohort of 154 patients. This cross sectional study has been completed by a prospective study for 40 patients evaluated at several time points. Results: The evaluation was performed in various situations: steady state i.e. no haematological complication, in MDS/AL and AA and lastly after HSCT. At the first evaluation, somatic mutation was found in 21 patients (30%) among the 70 in steady state and in 7 of the 8 cases with HC (6/6 cases with MDS/AL, in 1 among the 2 cases with AA) while the 1 of the 2 patients long term survivors after HSCT have no mutation and the other one kept a TP53 clone with a normal blood count and a low (1.5%) variant allele frequency (VAF). Among the 40 patients with several time points, 17 have a mutation at the first time points, but 10 others had additional mutation later. Globally, the most frequent gene involved was TP53 (82%) while mutations in other genes have been observed rarely. VAF in patients with vs without HC is lower (median VAF 0% vs 22.8% respectively p < 0.001) . Complex caryotype, monosomy 7, Iso7q were associated with P53 clone while in Del20q, 8 patients out 14 have a P53 mutations. The comparison between blood and bone marrow results allow the possibility to monitor such mutations in blood. Clonal evolution in one patient who presents a MDS in the course of the follow up had shown a competition between clones. Conclusion: Acquired TP53 is extremely frequent in patients with SBDS mutations, even in the absence of HC, but the prevalence as well as the VAF increased in case of HC. When sequential evaluation could be performed, competition between clones is frequent and a clinical decision remains therefore difficult, just on the evaluation of a time point. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Renard:Jazz Pharmaceuticals: Research Funding. Tournilhac:ABBVIE: Consultancy, Honoraria, Other: Travle grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant.

Published
2020

25. How Many Patients Have Congenital Neutropenia? a Population-Based Estimation from the Nationwide French Severe Chronic Neutropenia Registry

Author

Odile Fenneteau, Damien Bonnet, Jean Donadieu, Françoise Bachelerie, Jean Soulier, Despina Moshous, Laurence Faivre, Thierry Leblanc, Marlène Pasquet, Yves Bertrand, Nizar Mahlaoui, Blandine Beaupain, François Delhommeau, Nathalie Aladjidi, Hélène Lapillonne, Karl Balabanian, Hélène Cavé, Elodie Gouache, Fares bou Mitri, Thierry Lamy, Catherine Paillard, Virginie Gandemer, Flore Sicre de Fontbrune, Christine Bellanné-Chantelot, Sarah cohen Beaussant, Claire Fieschi, Aline Moignet Autrel, Wadih Abou Chahla, Philippe Labrune, and Vincent Barlogis

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Incidence (epidemiology), Immunology, Cell Biology, Hematology, Disease, medicine.disease, Biochemistry, Natural history, Autoimmune neutropenia, Epidemiology, medicine, Life expectancy, Medical genetics, Congenital Neutropenia, business
Abstract

Introduction: Congenital neutropenia (CN) is characterized by chronic neutropenia caused by a constitutional genetic defect and can be considered an orphan disease. Nationwide estimations of its incidence and prevalence are poorly documented but would provide key information to better follow-up of CN patients. Notably, orphan-drug status also is accorded based on such epidemiological parameters. Methods: The French Severe Chronic Neutropenia Registry (FSCNR) has prospectively enrolled CN patients since 1993, with multiple source verifications in France of that information: pediatric and adult hemato-immunology units, diagnostic labs... We also actively collect all cases followed in France, regardless of the healthcare facility monitoring the patient. To calculate incidence at birth, we considered subjects born between 1/1/1995 and 12/31/2017, because information completeness has been validated for this 22-year period. Number of births per year was provided by the French National Institute of Statistics and Economic Studies (INSEE). We used American College of Medical Genetics class 4 and 5 variants for genetic classification and the overall CN classification developed elsewhere.1 To estimate expected prevalence, we assumed 50-year life expectancy for these patients and compared ongoing enrolment to the prevalence estimation and calculated FNSCR coverage. A Poisson distribution was assumed. Results: On 15 July 2020, the FSCNR had identified 3205 patients. Reasons for non-enrolment of 2096 were, mainly: autoimmune neutropenia (n=501), foreign residency (n=214), other diagnosis (n=882) and diagnostic work-up not completed (n=249). Among the 1109 patients who fulfilled Chronic Neutropenia criteria, 242 had idiopathic neutropenia2 and 867 patients were considered to have CN1. Global results are presented in Table 1. In France, the CN incidence at birth (all subtypes combined) was 2.6×10-5 (95% CI: 2.04-2.8×10-5), which represents a mean of 23 new cases/year in a country with ~870,000 births/year. For all CN combined, the expected prevalence, assuming 50-year life expectancy, would be 1131 cases in a country of 65×106 inhabitants while the FCSNR currently has 867 cases enrolled or an estimated 77% nationwide coverage. Based on our results and our assumptions for life expectancy, estimated prevalence of CN for 10 millions inhabitants is therefore 174 CN. Genetic subtype representation is as follows: 20% SBDS, 17% ELANE (8% cyclic, 9% permanent), 9% GATA2, 7% SLC37A4, ~4-5% each of TAZ and CXCR4 and VPS13B, while the other subtypes are even rarer. At present, no cause has been identified for 25% of the cases. Conclusion: The results of this analysis provide an estimation of the major CN-descriptive epidemiological parameters and the relative frequencies of several subtypes. Despite the FSCNR's quite large registry, we estimate that about a quarter of the prevalent cases in France were missed, mainly those followed as adults. References 1 Donadieu J, Beaupain B, Fenneteau O, Bellanne-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br.J.Haematol. 2017; 179(4): 557-574. 2 Sicre De Fontbrune F, Moignet A, Beaupain B et al. Severe chronic primary neutropenia in adults: report on a series of 108 patients. Blood 2015; 126(14): 1643-1650. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. cohen Beaussant:X4 Pharmaceuticals, Inc.: Current Employment.

Published
2020

26. Liver involvement in patients with telomere-related genes mutations: prevalence, clinical, radiological, pathological features, outcome and risk factors

Author

Sabrina Sidali, Raphaël Borie, Sicre Flore, Elodie Lainey, Pierre-Emmanuel Rautou, Jacques Cadranel, Jean-marc Naccache, Vincent Cottin, Jérôme Dumortier, Emmanuel Jacquemin, Nousbaum Jean Baptiste, Sandrine Hirschi, Arnaud Bourdin, Magdalena Meszaros, Sebastien Dharancy, Sophie Hilaire, Vincent Mallet, Reynaud-Gaubert Martine, Louis Terriou, Frédéric Gottrand, Wadih Abou Chahla, Jean Emmanuel Khan, Paul Carrier, Faouzi Saliba, Laura Rubbia-Brandt, Laure Elkrief, Victor de Lédinghen, Armand Abergel, Tournilhac Olivier, Yasmina Chouik, Antoine Coupier, Thierry Leblanc, Isabelle Ollivier-Hourmand, Eric Nguyen Khac, Hélène Morisse-Pradier, Kinan El Husseini, Odile Goria, Ba Ibrahima, Dominique Roulot, Christophe Bureau, Hilario Nunes, Dominique Valla, Valérie Paradis, Kannengiesser Caroline, and Aurélie Plessier

Subjects
Hepatology
Published
2020

27. Genetic diagnosis of primary immunodeficiencies: A survey of the French national registry

Author

Nizar Mahlaoui, Capucine Picard, Perrine Bach, Laurence Costes, Virginie Courteille, Anja Ranohavimparany, Alexandre Alcaïs, Jean-Philippe Jais, Alain Fischer, Christine Bellanné-Chantelot, Jacinta Bustamante, Sylvie Chollet-Martin, Christian Drouet, Véronique Fremeaux-Bacchi, Caroline Kannengiesser, Virginie Girardin, Nathalie Lambert, Valérie Proulle, Jérémie Rosain, Marie José Stasia, Dominique Stoppa Lyonnet, Ioannis Theodorou, Wadih Abou-Chahla, Daniel Adoue, Nathalie Aladjidi, Zahir Amoura, Corinne Armari-Alla, Brigitte Bader-Meunier, Vincent Barlogis, Sophie Bayart, Yves Bertrand, Stéphane Blanche, Damien Bodet, Bernard Bonnotte, Raphaël Borie, Patrick Boutard, Claire Briandet, Jean-Paul Brion, Jacques Brouard, Liana Carausu, Emilie Catherinot, Nathalie Cheikh, Sarah Cohen-Beaussant, Louis-Jean Couderc, Pierre Cougoul, Gérard Couillault, Geneviève de Saint Basile, Catherine Devoldere, Anne Deville, Eric Dore, Fabienne Dulieu, Isabelle Durieu, Natacha Entz Werle, Claire Fieschi, Fanny Fouyssac, Pierre Frange, Vincent Gajdos, Lionel Galicier, Virginie Gandemer, Martine Gardembas, Catherine Gaud, Bernard Grosbois, Aurélien Guffroy, Corinne Guitton, Gaelle Guillerm, Eric Hachulla, Mohamed Hamidou, Sophie Haro, Yves Hatchuel, Olivier Hermine, Cyrille Hoarau, Bruno Hoen, Arnaud Hot, Sébastien Humbert, Arnaud Jaccard, Serge Jacquot, Rolland Jaussaud, Pierre-Yves Jeandel, Eric Jeziorski, Kamila Kebaili, Anne-Sophie Korganow, Olivier Lambotte, Fanny Lanternier, Claire Larroche, Alain Le Quellec, Emmanuelle Le Moigne, Vincent Le Moing, David Launay, Yvon Lebranchu, Marc Lecuit, Guillaume Lefevre, Richard Lemal, Valérie Li-Thiao-Te, Olivier Lortholary, Marion Malphettes, Aude Marie-Cardine, Nicolas Martin Silva, Agathe Masseau, Christian Massot, Françoise Mazingue, Etienne Merlin, Gérard Michel, Frédéric Millot, Béatrice Monlibert, Fabrice Monpoux, Despina Moshous, Luc Mouthon, Martine Munzer, Bénédicte Neven, Raphaëlle Nove-Josserand, Dalila Nouar, Eric Oksenhendler, Marie Ouachée-Chardin, Anne Pagnier, Marlène Pasquet, Isabelle Pellier, Yves Perel, Antoinette Perlat, Christophe Piguet, Dominique Plantaz, Pierre Quartier, Frédéric Rieux-Laucat, Pascal Roblot, Pierre-Simon Rohrlich, Bruno Royer, Valéry Salle, Françoise Sarrot-Reynauld, Amélie Servettaz, Jean-Louis Stephan, Nicolas Schleinitz, Felipe Suarez, Laure Swiader, Sophie Taque, Caroline Thomas, Olivier Tournilhac, Caroline Thumerelle, Jean-Pierre Vannier, Jean-François Viallard, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Service de Biostatistique et Informatique Médicale, Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Immunologie 'Autoimmunité et Hypersensibilités' [AP-HP Hôpital Bichat, Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche et d'Etude du Processus Inflammatoire (GREPI), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'immunologie [HEGP, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), the Study Center of Primary Immunodeficiencies, CHU Necker - Enfants Malades [AP-HP], Hémostase et biologie vasculaire, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital de la Tronche, Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hématogoie pédiatrique, hôpital Sud, SIGNAL-IMAGE-COMMUNICATION (SIC), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Pneumologie et Centre de Compétence des Maladies Pulmonaires Rares [AP-HP Hôpital Bichat, Paris], Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Pédiatrie Enfants - Hématologie Oncologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service des Maladies Infectieuses, CHU Grenoble, Service de Pédiatrie Médicale [Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Foch [Suresnes], Service de pédiatrie (CHU de Dijon), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Immunologie clinique [CHU St-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Médecine interne et immunologie clinique [Rennes] = internal medicine and clinical immunology [Rennes], CHU Pontchaillou [Rennes], Service d'Immunologie Clinique et de Médecine Interne, Centre National de Référence des Maladies Auto-immunes Rares, Hôpitaux Universitaires de Strasbourg, Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Claude Huriez [Lille], CHU Lille, Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), 'Personal Protection Against Vectors' working group (PPAV), PPAV working group, cellules dendritiques et greffes (JE 2448), Université de Tours (UT), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Service de Médecine Interne, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Médecine interne, maladies infectieuses, immunologie clinique, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut d’Hémato-Oncologie Pédiatrique, INSERM U1012, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Internal Medicine, Paris, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre collaborateur de l'OMS Listeria / WHO Collaborating Centre Listeria (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CHU Clermont-Ferrand, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Dept of Physiology, McGill University = Université McGill [Montréal, Canada], Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], American Memorial Hospital, American Memory Hospital, Department of Clinical Immunology, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service Immuno Hémato-Onco Pédiatrique, Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Pédiatrie médicale - Spécialités médicales [CHU Limoges], CHU Limoges, Service Hématologie Infantile, CHU Amiens-Picardie, Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Département de Médecine Interne, Immunologie clinique et maladies infectieuses [CHU Reims], Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de médecine de l'enfant et de l'adolescent [CHU Rennes], Clinical Haematology, CHU Hôtel-Dieu, Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], French Ministry of Health, LFB, GlaxoSmithKlineGlaxoSmithKline, CSL BehringCSL Behring, ShireShire, Octapharma, Binding Site, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Chaire Médecine expérimentale (A. Fischer), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), GREPI, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pasteur [Paris]-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie pédiatrique, CHU Toulouse [Toulouse], CHU Saint-Etienne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de médecine de l'enfant et de l'adolescent, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Nutrition et Neurobiologie intégrée (NutriNeur0), Ecole nationale supérieure de chimie, biologie et physique-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1-Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Sud, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose et Progression tumorale (CRCNA / Equipe 9), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Service de médecine interne, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Tours, Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre collaborateur de l'OMS Listeria - Biologie des Infections (CCOMS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], McGill University, Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche sur le Cancer Nantes-Angers (LUNAM), Université d'Angers (UA)-Université de Nantes (UN), Centre Hospitalier Universitaire d'Amiens (CHU), centre hospitalier universitaire amiens, CHU Bordeaux [Bordeaux]-Université Sciences et Technologies - Bordeaux 1, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC)

Subjects
0301 basic medicine, Primary Immunodeficiency Diseases, medicine.medical_treatment, Genetic counseling, Immunology, Genomics, Bioinformatics, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Genotype, Humans, Immunology and Allergy, Medicine, Genetic Testing, Registries, Retrospective Studies, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, Common variable immunodeficiency, Retrospective cohort study, medicine.disease, Phenotype, 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030104 developmental biology, Identification (biology), France, business, 030215 immunology
Abstract

International audience; To the Editor:Since the mid-1980s, continuous progress in genetics and genomics has accelerated the rapid identification of causative genetic variants leading to primary immunodeficiencies (PIDs; >300 genes),1 with the noticeable exception of B-cell disorders, such as common variable immunodeficiency (CVID). The identification of these mutations not only validates a clinical diagnosis but also is useful in several other respects (more accurate prognosis on phenotype/genotype correlation, targeted therapy, and genetic counseling). [...]

Published
2019

28. In vitro analysis of overall particulate contamination exposure during multidrug IV therapy: Impact of infusion sets

Author

Gilles Lebuffe, Pascal Odou, Maxime Perez, Christine Barthélémy, Wadih Abou Chahla, Brigitte Nelken, and Bertrand Décaudin

Subjects
Drug, business.industry, Lymphoblastic Leukemia, media_common.quotation_subject, Hematology, Pharmacology, medicine.disease, In vitro analysis, Leukemia, Drug concentration, Oncology, Pediatrics, Perinatology and Child Health, medicine, Vancomycin, business, Particulate contamination, medicine.drug, media_common, Piperacillin
Abstract

Background Drug incompatibilities, recognizable through precipitate, may have clinical consequences for patients, especially during multidrug IV therapies, where vancomycin and piperacillin are present. Drug concentration and infusion set influence the overall particulate contamination of pediatric infusion protocols. The use of multi-lumen infusion sets could prevent such incompatibilities. Our goal was to define and assess a new way to infuse these drugs during leukemia treatment in children. Procedures This in vitro study focused on a pediatric multidrug protocol for patients diagnosed with lymphoblastic leukemia and receiving allogeneic transplantation. Different vancomycin concentrations were tested to infuse incompatible drugs simultaneously without any particle formation (optimized multidrug protocol). A dynamic particle count test was used over 24 hr to evaluate the overall particulate contamination of our standard and optimized multidrug protocols, using both a standard and a multi-lumen infusion set. Results No visible particles were detected on a decreased vancomycin concentration compared to the standard dose. For the optimized multidrug protocol, the use of a multi-lumen infusion set reduced overall particulate contamination by 68%, compared to the standard infusion set (P = 0.002). Large-sized particles were significantly reduced when using the multi-lumen infusion set approximately 60% (P = 0.027) and 90% (P = 0.009) for particle sizes ≥10 μm and 25 μm, respectively. Conclusions This study demonstrates that a large number of particles can be administered during parenteral multidrug infusion. The choice of drug concentration and/or the type of infusion set may reduce this. Further studies are required to evaluate adverse clinical effects. Pediatr Blood Cancer 2015;62:1042–1047. © 2015 Wiley Periodicals, Inc.

Published
2015

29. Alemtuzumab as First Line Treatment in Children with Familial Lymphohistiocytosis

Author

Eric Jeziorski, Bénédicte Neven, Pierre-Simon Rohrlich, Isabelle Pellier, Vincent Barlogis, Caroline Elie, Stéphanie Chhun, Yves Bertrand, Geneviève de Saint Basile, Laurent Dupic, Caroline Thomas, Mathieu Fusaro, Wadih Abou Chahla, Bénédicte Bruno, Guillaume Morelle, Alain Fischer, Martin Castelle, Jean Louis Stephan, Despina Moshous, Catherine Paillard, Capucine Picard, Aude Marie-Cardine, Stéphane Blanche, and Coralie Briand

Subjects
medicine.medical_specialty, Hemophagocytic lymphohistiocytosis, education.field_of_study, business.industry, medicine.medical_treatment, Immunology, Population, Cell Biology, Hematology, Hematopoietic stem cell transplantation, medicine.disease, Biochemistry, Tolerability, Intensive care, Internal medicine, Clinical endpoint, medicine, Alemtuzumab, education, Prospective cohort study, business, medicine.drug
Abstract

Background Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory condition caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting an excess of inflammatory cytokines. When untreated, primary HLH is invariably fatal. Treatment requires the achievement of remission of HLH prior to allogeneic hematopoietic stem cell transplantation. Despite significant treatment progress, pre-HSCT mortality remains a challenge. In the Etoposide-based HLH-94 and HLH-2004 studies pre-HSCT mortality was 27% and 19%, respectively. A better understanding of the pathophysiology of primary HLH has opened new avenues for targeted immunotherapy. Based on our previous observation concerning the use of Antithymoglobulin in HLH, we propose a new therapeutic strategy with Alemtuzumab in association with steroids and cyclosporine A (CSA) as first line treatment in primary HLH. In contrast to ATG, Alemtuzumab does not activate T lymphocytes while killing them. Therefore, we expect a better tolerance and efficacy of Alemtuzumab. This may have a positive impact not only on survival until HSCT, but also on overall survival and quality of life, especially with regard to long-term neurological sequelae. Methods 24 consecutive treatment naïve patients with genetically confirmed primary HLH had received first line Alemtuzumab in association to steroids and CSA from 01/2009 to 06/2015 in the Unit for Pediatric Immunology in Necker Hospital Paris, as well as two additional patients in 10/2016 and 10/2018 respectively, who could not be included in the prospective trial. From 06/2015 to 06/2019, 29 patients have been enrolled in a multicenter, open, phase I/II, non-comparative, non randomized study (NCT02472054). Patients with lymphohistiocytic activation syndrome who had not received any specific treatment prior to enrollment except steroids and CSA were included. Treatment consisted in intravenous administration of Alemtuzumab in association to Methylprednisolone and CSA. The primary outcome measures is the number of surviving patients until HSCT, secondary outcome measures the number of complete remissions following treatment at Day (D)14, D21, D28. To assess the efficacy of the Alemtuzumab, the time of delay between the first administration of Alemtuzumab and complete remission will be determined. Alemtuzumab Pharmacokinetics will be done. All adverse events are reported. Results Retrospective analysis of 26 patients (pilot study): The median age of patients was 1.9 months (birth - 7 years), 6 patients were neonates. When Alemtuzumab was started, out of 26 patients 12 (46.1%) required intensive care, 8 (30.7%) mechanical ventilation, 13 (50%) had neurological involvement, 9 (34.6%) hepatocellular insufficiency. One 2-month-old Munc13-4 patient died at H+48 after two administrations of Alemtuzumab (total dose 1.5mg/kg) for hepatic failure and acute renal failure. A second patient with Perforin deficiency did not respond neither to three courses of Alemtuzumab (cumulative dose 6.5mg/kg) nor repeated Etoposid, 40mg/kg ATG, or Ruxulotinib. He died at D+65. The 24 remaining patients survived until HSCT (survival 92.3%). As shown in the figure, two patients required additional treatment. Overall 22 patients achieved CR, 2 PR at the time of HSCT. The prospective study enrolled 29 patients from 06/2015 to 06/2019. Median age at onset of HLH was 0.5 years (range 0.02 to 17.2 years), one patient withdrawed consent. 12 patients received one course, 13 two, 2 three and one patient 4 courses of Alemtuzumab. 24 patients with a genetic confirmed HLH predisposition reached the primary endpoint with 22 surviving until HSCT (91,6%). One patient is still awaiting HSCT. The three remaining patients are one CA-EBV patient and a newborn with secondary HLH due to fulminant HSV hepatitis, who both died, as well as a patient with predominant neurological HLH without genetic diagnosis who is in sustained remission without any specific treatment. Detailed results from the completed study will be presented. Conclusions This is the first report on Alemtuzumab as first line approach in the treatment of primary HLH. Our results in more than 50 pediatric patients treated in a pilot study and prospective trial indicate that Alemtuzumab allows controlling HLH activity with a favorable safety and tolerability profile in a very fragile population. 92.3% and 91.6% of patients respectively survived to HSCT. Figure Disclosures No relevant conflicts of interest to declare. Off Label Disclosure: Alemtuzumab (Campath) has been used in a prospective trial to evaluate its efficacy as first line treatment in Familial Lymphohistiocytosis.

Published
2019

30. Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia

Author

Guillaume Grzych, Catherine Roche-Lestienne, Claude Preudhomme, Gauthier Decool, Nicolas Duployez, Elise Boudry-Labis, Wadih Abou Chahla, and Nathalie Grardel

Subjects
Genetics, Poor prognosis, medicine.medical_specialty, RUNX1, business.industry, BCP-ALL, Cytogenetics, General Medicine, Case Reports, cytogenetics, Molecular cytogenetics, SNP-array, chemistry.chemical_compound, Pediatric Acute Lymphoblastic Leukemia, chemistry, Cancer research, medicine, SNP, Chromosome 21, business, SNP array, iAMP21
Abstract

Key Clinical Message Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.

Published
2015

31. NUP214-ABL1 fusion defines a rare subtype of B-cell precursor acute lymphoblastic leukemia that could benefit from tyrosine kinase inhibitors

Author

Guillaume Grzych, Brigitte Nelken, Nicolas Duployez, Claude Preudhomme, Nathalie Grardel, Bénédicte Bruno, Emmanuelle Clappier, Martin Alarcon Fuentes, Benoît Ducourneau, Wadih Abou Chahla, and Thomas Boyer

Subjects
Treatment response, medicine.medical_specialty, ABL, Lymphoblastic Leukemia, Proto-Oncogene Proteins c-abl, Cytogenetics, Hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, Gene expression, Immunology, Cancer research, medicine, Online Only Articles, Tyrosine kinase, B cell, 030215 immunology
Abstract

Acute lymphoblastic leukemia (ALL) comprises multiple entities with distinct clinico-biological features and treatment response. Among prognostic factors, cytogenetics remains one of the most discriminating parameters and is currently used to determine risk and treatment stratification. However

Published
2015

32. Ostéomyélite récidivante révélant un syndrome myélodysplasique avec mutation GATA2

Author

Aurélie Mezel, François Dubos, Wadih Abou Chahla, Capucine Trochu, Aline Renneville, Caroline Petyt, Françoise Mazingue, and Afane Brahimi

Subjects
Oncology, Pediatrics, Perinatology and Child Health, Hematology
Abstract

Il a ete recemment decrit des mutations du gene GATA2 avec des consequences cliniques variees : lymphœdeme, auto-immunite, deficit immunitaire, cancers (tumeurs solides et hemopathies malignes), affections pulmonaires. Les infections recidivantes notamment a mycobacteries atypiques sont frequemment decrites : syndrome MonoMAC. L’identification de ces mutations permet une prise en charge adaptee ainsi qu’un conseil genetique. Nous rapportons le cas d’un patient de 14 ans hospitalise en novembre 2014 pour prise en charge d’une osteomyelite humerale a Staphylococcus aureus traitee par curetage chirurgical et antibiotherapie par clindamycine et levofloxacine. En fevrier 2015, recidive d’osteomyelite qui avait necessite une nouvelle intervention chirurgicale ainsi qu’une reprise du traitement antibiotique. Plusieurs anomalies etaient decouvertes a l’hemogramme diagnostique (macrocytose VGM 103 μ3, neutropenie 0,8 G/L, monocytopenie 0,1 G/L, thrombopenie 112 G/L). Les myelogrammes successifs montraient une dysmyelopoiese avec un exces de mastocytes. Au caryotype medullaire, il existait un clone avec monosomie 7 : 45, XY, –7. Nous suspections une haplo-insuffisance de GATA2 suite a un 3e episode d’osteomyelite en aout 2015. Un traitement antibiotique anti-mycobacterie atypique d’epreuve de 6 semaines par clarythromycine, rifampicine et moxifloxacine etait instaure et a permis une amelioration clinique. L’analyse en biologie moleculaire confirme une mutation pathogene de GATA2 c.915_916delCT, p.W306AfsX77. Une greffe de moelle osseuse est prevue pour la prise en charge de cette hemopathie constitutionnelle.

Published
2015

33. In vitro analysis of overall particulate contamination exposure during multidrug IV therapy: impact of infusion sets

Author

Maxime, Perez, Bertrand, Décaudin, Wadih, Abou Chahla, Brigitte, Nelken, Christine, Barthélémy, Gilles, Lebuffe, and Pascal, Odou

Subjects
Drug Incompatibility, Humans, Particle Size, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Drug Contamination, Infusions, Intravenous
Abstract

Drug incompatibilities, recognizable through precipitate, may have clinical consequences for patients, especially during multidrug IV therapies, where vancomycin and piperacillin are present. Drug concentration and infusion set influence the overall particulate contamination of pediatric infusion protocols. The use of multi-lumen infusion sets could prevent such incompatibilities. Our goal was to define and assess a new way to infuse these drugs during leukemia treatment in children.This in vitro study focused on a pediatric multidrug protocol for patients diagnosed with lymphoblastic leukemia and receiving allogeneic transplantation. Different vancomycin concentrations were tested to infuse incompatible drugs simultaneously without any particle formation (optimized multidrug protocol). A dynamic particle count test was used over 24 hr to evaluate the overall particulate contamination of our standard and optimized multidrug protocols, using both a standard and a multi-lumen infusion set.No visible particles were detected on a decreased vancomycin concentration compared to the standard dose. For the optimized multidrug protocol, the use of a multi-lumen infusion set reduced overall particulate contamination by 68%, compared to the standard infusion set (P = 0.002). Large-sized particles were significantly reduced when using the multi-lumen infusion set approximately 60% (P = 0.027) and 90% (P = 0.009) for particle sizes ≥10 μm and 25 μm, respectively.This study demonstrates that a large number of particles can be administered during parenteral multidrug infusion. The choice of drug concentration and/or the type of infusion set may reduce this. Further studies are required to evaluate adverse clinical effects.

Published
2014

34. Chédiak-Higashi syndrome: brain MRI and MR spectroscopy manifestations

Author

Gustavo Soto Ares, Wadih Abou Chahla, Valentina Lolli, Jean-Pierre Pruvo, and Patrice Jissendi-Tchofo

Subjects
In vivo magnetic resonance spectroscopy, Male, Pathology, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Contrast Media, Gadolinium, Dexamethasone, Recurrence, hemic and lymphatic diseases, medicine, Humans, Radiology, Nuclear Medicine and imaging, Child, Immunodeficiency, Neuroradiology, Hemophagocytic lymphohistiocytosis, medicine.diagnostic_test, business.industry, Echo-Planar Imaging, Chédiak–Higashi syndrome, Metabolic disorder, Brain, Magnetic resonance imaging, medicine.disease, Image Enhancement, Oculocutaneous albinism, Magnetic Resonance Imaging, Diffusion Magnetic Resonance Imaging, Methotrexate, Treatment Outcome, Pediatrics, Perinatology and Child Health, Cyclosporine, business, Chediak-Higashi Syndrome, Immunosuppressive Agents, Follow-Up Studies
Abstract

Chediak-Higashi syndrome is a rare inherited metabolic disorder characterized by partial oculocutaneous albinism, immunodeficiency, and neurological dysfunction. We present the brain magnetic resonance imaging (MRI) and MR spectroscopy (MRS) findings obtained during the accelerated phase of the disorder in an 8-year-old. The brain MRI manifestations at recurrences 15 months and 24 months later are reported as well.

Published
2014

35. Utilisation des inhibiteurs de tyrosine kinase dans un cas de leucémie aiguë lymphoblastique de type B présentant une fusion NUP214-ABL1

Author

Thomas Boyer, Guillaume Grzych, Bénédicte Bruno, Martin Alarcon Fuentes, Nicolas Duployez, Emmanuelle Clappier, Brigitte Nelken, Claude Preudhomme, Nathalie Grardel, and Wadih Abou Chahla

Subjects
Oncology, Pediatrics, Perinatology and Child Health, Hematology
Abstract

Nous rapportons le cas d’une jeune fille de 15 ans presentant une leucemie aigue lymphoblastique de type B. La premiere ligne de traitement suivie selon l’EORTC 58 081 est marquee par une cortico et une chimioresistance. Une allogreffe de moelle osseuse permet une premiere remission complete mais la patiente rechute 5 mois apres. Une seconde ligne de traitement suivant le protocole BOREALL se revele etre un echec. Devant cette impasse therapeutique, la patiente est consideree en soin palliatif pendant 11 mois. Retrospectivement, une analyse par technique de SNP-array realisee sur le prelevement initial de moelle met en evidence une fusion NUP214-ABL1 . Considerant l’implication de la tyrosine kinase ABL1 dans ce rearrangement, un traitement a base de Dasatinib ® et de chimiotherapies adjuvantes est debute, entrainant une seconde remission complete.

Published
2015

36. Erratum to: Chédiak-Higashi syndrome: brain MRI and MR spectroscopy manifestations

Author

Patrice Jissendi-Tchofo, Gustavo Soto Ares, Valentina Lolli, Jean-Pierre Pruvo, and Wadih Abou Chahla

Subjects
Leukopenia, business.industry, Anemia, viruses, Chédiak–Higashi syndrome, virus diseases, medicine.disease_cause, medicine.disease, Molecular biology, Virus, Herpes simplex virus, Cerebrospinal fluid, Pediatrics, Perinatology and Child Health, Medicine, Radiology, Nuclear Medicine and imaging, Platelet, Hemoglobin, medicine.symptom, business
Abstract

“Laboratory investigations revealed leukopenia [white blood cells: 3,500 to 10,500/mm3 (normal values: 3,500 to 10,500/ mm3), polymorphonucleates: 1,500 cells/mm3 (normal values: ≥ 1,500 cells/mm3)], anemia [hemoglobin: 13.5 to 17.5 g/dL], and a relative decrease of thrombocytes [platelets: 169,000/mm3 (normal values: between between 150 and 400/ mm3]. Polymerase-chain-reaction tests failed to reveal evidence of herpes simplex virus, enterovirus, cytomegalovirus, varicella-zoster virus, Epstein-Barr virus or adenovirus. Cerebrospinal fluid analysis showed 24 nucleated cells consisting with lymphocytes [normal values: (×10-6/L)

Published
2015

37. Haematological features of telomere biology disorders diagnosed in adulthood: A French nationwide study of 127 patients.

Author

Maillet, François, Galimard, Jacques‐Emmanuel, Borie, Raphaël, Lainey, Elodie, Larcher, Lise, Passet, Marie, Plessier, Aurélie, Leblanc, Thierry, Terriou, Louis, Lebon, Delphine, Alcazer, Vincent, Cathebras, Pascal, Loschi, Michael, Wadih, Abou‐Chahla, Marcais, Ambroise, Marceau‐Renaut, Alice, Couque, Nathalie, Lioure, Bruno, Soulier, Jean, and Ba, Ibrahima

Subjects
*ACUTE myeloid leukemia, *SOMATIC mutation, *MYELODYSPLASTIC syndromes, *BONE marrow, *OVERALL survival
Abstract

Summary Data on haematological features of telomere biology disorders (TBD) remain scarce. We describe haematological, extra‐haematological characteristics and prognosis of 127 genetically confirmed TBD patients diagnosed after the age of 15. Ninety‐three index cases and 34 affected relatives were included. At diagnosis of TBD, 76.3% of index cases had haematological features, half pulmonary features and a third liver features. At diagnosis, bone marrow failure (BMF) was present in 59 (46.5%), myelodysplastic syndrome (MDS) in 22 (17.3%) and acute myeloid leukaemia (AML) in 2 (1.6%) while 13 (10.2%) developed or worsened bone marrow involvement during follow‐up. At diagnosis, compared to MDS/AML patients, BMF patients were younger (median 23.1 years vs. 43.8, p = 0.007), and had a better outcome (4‐year overall survival 76.3% vs. 31.8%, p < 0.001). While frequencies and burden of cytogenetical and somatic mutations increased significantly in myeloid malignancies, some abnormalities were also observed in patients with normal blood counts and BMF, notably somatic spliceosome variants. Solid cancers developed in 8.7% patients, mainly human papillomavirus‐related cancers and hepatocellular carcinomas. TBD is a multiorgan progressive disease. While BMF is the main haematological disorder, high‐risk myeloid malignancies are common, and are, together with age, the only factors associated with a worse outcome. [ABSTRACT FROM AUTHOR]

Published
2024
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