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1. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients

Author

Lucie Hernandez, Samuel Quentin, Elodie Lainey, Thierry Leblanc, Nicolas Boissel, Etienne Lengliné, Jean-Hugues Dalle, Julien Masliah-Planchon, Gérard Michel, Lionel Adès, Régis Peffault de Latour, Louis De Jaegere, Yves Bertrand, André Baruchel, Guy Leverger, Marie Sebert, Naddia Vasquez, Emmanuelle Clappier, Marc Muller, Olivier Bluteau, Stéphane Blanche, Isabelle Pellier, Gérard Socié, Wendy Cuccuini, Carine Domenech, Mathilde Hunault, Nicolas Blin, Raphael Itzykson, Sébastien Maury, Pierre Fenaux, Bénédicte Bruno, Mélanie Da Costa, Anna Raimbault, Jean Soulier, Claudine Schmitt, Arnaud Petit, Flore Sicre de Fontbrune, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Recherche clinique appliquée à l'hématologie (URP_3518), Département de Néphrologie et transplantation [Hôpital Saint Louis - APHP], 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), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Service d'hématologie pédiatrique [Robert-Debré - APHP], Institut Universitaire d'Hématologie [Hôpital Saint-Louis - APHP], Laboratoire d’Hématologie [CHU Henri-Mondor - APHP], CHU Henri Mondor, Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique [CHRU Nancy], Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Département d'Hématologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'Hématologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service d'Immunologie Hématologie et Oncologie pédiatriques [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université Paris Cité (UPCité), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Henri Mondor [Créteil], 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)-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), and Bernardo, Elizabeth

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, MECOM, DNA Mutational Analysis, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, Cohort Studies, 03 medical and health sciences, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Fanconi anemia, Internal medicine, hemic and lymphatic diseases, Exome Sequencing, medicine, Humans, Child, Bone Marrow Diseases, Germ-Line Mutation, Exome sequencing, Chromosome 7 (human), business.industry, Infant, Newborn, Bone marrow failure, High-Throughput Nucleotide Sequencing, Infant, Cell Biology, Hematology, medicine.disease, Pancytopenia, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, Myelodysplastic Syndromes, Female, Bone marrow, business
Abstract

International audience; Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

Published
2018
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2. NAP1L1-MLLT10 is a rare recurrent translocation that is associated with HOXA activation and poor treatment response in T-cell acute lymphoblastic leukaemia

Author

Aurore Touzart, Tony Marchand, Agata Cieslak, Marc Muller, Jonathan Bond, Elizabeth Macintyre, Martine Escoffre, Claudine Schmitt, Vahid Asnafi, Thierry Fest, Audrey Contet, Amélie Trinquand, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - 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), Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de Transplantation Médullaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital d'enfants, Service de Médecine Nucléaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie Pédiatrique [CHRU Nancy], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), B, AT, AC, AT, MM and TF performed and interpreted diagnostic investigations. TM, ME, AC and CS provided clinical care and interpreted clinical data. JB, VA and EAM analysed and collated data and wrote the manuscript. JB is supported by a Kay Kendall Leukaemia Fund Intermediate Research Fellowship. The Macintyre laboratory is supported by the Association Laurette Fugain and the INCa CARAMELE Translational Research and PhD Programmes., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Médecine Nucléaire [Nancy], 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 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Hôpital d'enfants, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
0301 basic medicine, acute leukaemia, Treatment response, NAP1L1, [SDV]Life Sciences [q-bio], MEDLINE, Chromosomal translocation, HOXA, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Text mining, Medicine, clinical aspects, Young adult, leukaemia cytogenetics, ComputingMilieux_MISCELLANEOUS, [ SDV ] Life Sciences [q-bio], business.industry, biology, T-cell acute lymphoblastic leukaemia, Hematology, 3. Good health, 030104 developmental biology, Cancer research, business, 030215 immunology
Abstract

International audience; no abstract

Published
2016
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3. Pharmacokinetic and Pharmacodynamic Characterization of Graspa Versus Native L-Asparaginase in Combination with Cooprall Chemotherapy in a Phase 3 Randomized Trial for the Treatment of Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01 51851 7)

Author

Thomas, Xavier, Bertrand, Yves, Baruchel, Andre, Blin, Nicolas, Tavernier, Emmanuelle, Ducassou, Stephane, Norbert Vey, Gandemer, Virginie, Cacheux, Victoria, Mazingue, Francoise, Raffoux, Emmanuel, Plat, Genevieve, Fernandes, Jose, Poiree, Maryline, Fornecker, Luc, Stephan, Jean-Louis, Hunault, Mathilde, Auvrignon, Anne, Leguay, Thibault, Lepretre, Stephane, Ferster, Alina, Pellier, Isabelle, Plouvier, Emmanuel, Schmitt, Claudine, Bonin, Cecile, Godfrin, Yann, El Hariry, Iman, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Hôpital Pellegrin Tripode, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), 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), CHU Clermont-Ferrand, Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'hématologie pédiatrique, CHU Saint-Etienne, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Rennes 1 (UR1), and 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 )

Subjects
[SDV]Life Sciences [q-bio]
Abstract

WOS:000368020102004; International audience; Conference: 57th Annual Meeting of the American-Society-of-Hematology - Orlando, FL - DEC 05-08, 2015

Published
2015

4. Updated Clinical Activity of Graspa Versus Native l-Asparaginase in Combination with Cooprall Regimen in Phase 3 Randomized Trial in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Author

José Fernandes, Thibault Leguay, Norbert Vey, Stéphane Ducassou, Stéphane Leprêtre, Jean-Louis Stephan, Emmanuelle Tavernier, Iman El Hariry, Emmanuel Plouvier, Geneviève Plat, Poiree Maryline, Dominique Plantaz, Cecile Bonin, Anne Auvrignon, Xavier Thomas, Yves Bertrand, Claudine Schmitt, Françoise Mazingue, Alina Ferster, Luc Fornecker, Mathilde Hunault, Victoria Cacheux, Nicolas Blin, Emmanuel Raffoux, André Baruchel, Isabelle Pellier, Virginie Gandemer, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Pellegrin Tripode, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), 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), CHU Clermont-Ferrand, Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie pédiatrique, CHU Saint-Etienne, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Hématologie Infantile, CHU Grenoble, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Oncology, medicine.medical_specialty, Pediatrics, Asparaginase, [SDV]Life Sciences [q-bio], Immunology, 02 engineering and technology, Biochemistry, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Randomized controlled trial, law, Internal medicine, Acute lymphocytic leukemia, medicine, In patient, Adverse effect, 030304 developmental biology, 0303 health sciences, Surrogate endpoint, business.industry, Cell Biology, Hematology, 021001 nanoscience & nanotechnology, medicine.disease, Chemotherapy regimen, 3. Good health, Regimen, chemistry, 0210 nano-technology, business
Abstract

Background Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (proposed eryaspase, E-Coli L-Asparaginase encapsulated into red blood cells) improves pharmacokinetics, tolerability and maintain circulating asparaginase (ASPA) activity due to the protective barrier of the erythrocyte membrane. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL. In the non-allergic pts, GRASPA significantly reduced the incidence of hypersensitivity (0% vs 46%; p100 IU/l was 21 ± 5 vs 9 ± 7 days in GRASPA and L-ASP, respectively (p Methods This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the duration of ASPA activity > 100IU/L and the incidence of hypersensitivity during induction. Key secondary endpoints were complete remission, minimal residual disease, relapse rate, event free survival (EFS) and overall survival (OS). Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n= 28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C). All pts received COOPRALL protocol as a backbone chemotherapy. Results A total of 80 pts with relapsed and or refractory ALL were enrolled into the trial. There were a greater proportion of pts who completed the induction treatment in GRASPA arm (65%) than in the L-ASP arm (46%). The main reasons for treatment discontinuation were: target levels of asparagine depletion not reached (64%) in GRASPA arm, and adverse events (58%) in the L-ASP arm. In addition, in the L-ASP arm, 5 (19%) pts prematurely discontinued treatment due to disease progression. As of the cut-off date (28th August 2014), the majority of pts (63%) still continued in the study and followed-up for survival. The relapse rate at 6 and 12 mo was low, and accounted for 3 (13%; 95% CI: 2.6; 32.4) and 5 (26%; 95% CI: 9.1; 51.2) in the GRASPA arm, compared to 1 pt (5%) and 3 (17%; 95% CI: 3.6; 41.4) in the L-ASP arm, respectively. Except for L-ASP, and adult patients, the median EFS and OS were not reached for GRASPA in the entire set or in children, either at 12 months. Overall, there was a trend across all groups with lower EFS and OS event rates with GRASPA compared to L-ASP, as presented in table below. The 2-year follow up will be additionally provided at the meeting Table 1. GRASPA vs L-ASP All patients GRASPA = 26 L-ASP = 28 Children GRASPA = 21 L-ASP = 21 Adults GRASPA = 5 L-ASP = 7 12 mo EFS Median (mo) NR vs 11.6 NR 4.6 vs 1.6 Events 30.8% vs 50.0% 19.1% vs 38.1% 80% vs 85.7% HR 0.54 0.47 0.69 95% CI 0.23; 1.26 0.15; 1.47 0.20; 2.44 P Value* 0.153 0.196 0.569 12 mo OS Median (mo) NR NR 10 vs 8.2 Events 23.1% vs 32.1% 4.8% vs 14.3% 20% vs 42.8% HR 0.63 0.34 0.39 95% CI 023; 1.74 0.05; 2.42 0.05; 2.81 P Value* 0.377 0.424 0.705 *P value in all subsets is not statistically significant Conclusion GRASPA has demonstrated both safety and activity in pts with relapsed ALL, and provides an alternative treatment option for those patients. Disclosures Bertrand: ERYTECH Pharma: Consultancy. Thomas:ERYTECH Pharma: Consultancy. Vey:Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Bonin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

Published
2015

5. Evaluation of the Impact of the Presence of Neutralizing L-Asparaginase Antibodies on the Efficacy and Safety of Graspa in Phase 3 Randomized Trial Versus Native L-Asparaginase in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Author

Yves Bertrand, Françoise Mazingue, Cecile Bonin, Mathilde Hunault, Yann Godfrin, Anne Auvrignon, Claudine Schmitt, Jean-Louis Stephan, Dominique Plantaz, Emmanuel Raffoux, José Fernandes, Nicolas Blin, Geneviève Plat, Thibault Leguay, Maryline Poiree, Emmanuel Plouvier, Alina Ferster, Emmanuelle Tavernier, Xavier Thomas, André Baruchel, Stéphane Ducassou, Luc Fornecker, Victoria Cacheux, Stéphane Leprêtre, Iman El Hariry, Norbert Vey, Isabelle Pellier, Virginie Gandemer, Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Pellegrin Tripode, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pediatric Onco-Hematology Unit, 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 ), CHU Clermont-Ferrand, Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'hématologie pédiatrique, CHU Saint-Etienne, CHU Pitié-Salpêtrière [AP-HP], CHU Trousseau [APHP], Service Hématologie Infantile, CHU Grenoble, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Oncology, Asparaginase, medicine.medical_specialty, Lymphoblastic Leukemia, [SDV]Life Sciences [q-bio], Immunology, 02 engineering and technology, 030226 pharmacology & pharmacy, Biochemistry, law.invention, L asparaginase, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Acute lymphocytic leukemia, Internal medicine, medicine, In patient, biology, business.industry, Cell Biology, Hematology, 021001 nanoscience & nanotechnology, medicine.disease, Chemotherapy regimen, 3. Good health, chemistry, biology.protein, Antibody, 0210 nano-technology, business
Abstract

Background Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (eryaspase - proposed INN) is an L-asparaginase encapsulated into the red blood cells. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL. Methods This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the mean duration of asparaginase (ASPA) activity > 100 IU/L and incidence of hypersensitivity reactions during induction phase. Key secondary endpoints were safety, tolerability, complete remission and minimal residual disease rate, PK, and anti-ASPA antibodies (A-Abs) at baseline. Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n=28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C). All pts received COOPRALL protocol as a backbone chemotherapy. Here we report the impact of A-Abs on safety and efficacy of GRASPA. Assessments were performed at Day 4, 13, 18, and 27 (F1/F2 block), Day 6, 15, and 27 (VANDA block), and Day 6, 12 (R2/R1 block). Results At baseline, 23%, 25%, and 58% of pts had +ve A-Abs status in Arms A, B, and C, respectively. The mean duration of total ASPA activity (Days) adjusted for baseline antibody status is presented below, and shows that activity slightly differed with positive status; however, GRASPA maintained higher activity compared to L-ASP: Table 1. GRASPA L-ASP GRASPA L-ASP GRASPA (Arm C) Antibody status Negative Positive Negative Positive N 20 21 6 7 11 15 Mean (SD) 22.4 (3.6) 10.31 (8.1) 14.17 (5.1) 6.5 (4.0) 18.9 (6.8) 18.4 (6.2) Median 22.4 8.3 12.2 7.0 21.8 21.7 Min; Max 10.2; 30.7 0.0; 25.0 9.8; 21.8 1.9; 14.0 9.1; 27.9 6.9; 25.0 The incidence of hypersensitivity reactions were 0%, 7/21 (33%), and 2/11 (18%) in pts with negative A-Abs, compared to 0%, 6/7 (85.7%), and 1/15 (7%) in pts with positive A-Abs, in arms A, B and C, respectively. The CR rate during induction was 75%, 48%, and 64% in pts with negative A-Abs, compared to 33%, 14% and 48% in pts with positive A-Abs, in arms A, B and C, respectively. Conclusion These results show that about one third of pts without evidence of prior hypersensitivity have silent A-Abs activation. Positive A-Abs appeared to attenuate the clinical activity in all treatments arms. GRASPA consistently demonstrated activity and improved hypersensitivity regardless of A-Abs status, and therefore, GRASPA is a suitable option for patients with relapsed ALL. Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thomas:ERYTECH Pharma: Consultancy. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Bonin:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

Published
2015

6. Late cardiomyopathy in childhood acute myeloid leukemia survivors: a study from the LEA program

Author

Gérard Michel, Pascal Chastagner, Guy Leverger, Maya Allouche, Yves Bertrand, Marie-Dominique Tabone, Hervé Chambost, Vincent Barlogis, Camille Vercasson, Laure Saumet, André Baruchel, Sandrine Thouvenin-Doulet, Maryline Poiree, Dominique Plantaz, Pascal Auquier, Justyna Kanold, Julie Berbis, Claire Oudin, Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Service d'hématologie, CHU Lyon, Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service Hématologie Infantile, CHU Grenoble, Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Clermont-Ferrand-CIC Inserm 501, 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), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Montpellier, Department of Clinical Hematology, Montpellier, France, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and HAL AMU, Administrateur

Subjects
CHILDREN, Kaplan-Meier Estimate, THERAPY, 0302 clinical medicine, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, ADOLESCENTS, Cumulative incidence, Survivors, Child, RISK, Acute leukemia, Incidence, Childhood Acute Myeloid Leukemia, Hematology, Leucemie Enfant & Adolescent program, CANCER, 3. Good health, Leukemia, Myeloid, Acute, 030220 oncology & carcinogenesis, Child, Preschool, France, Cardiomyopathies, medicine.drug, medicine.medical_specialty, Anthracycline, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, late cardiomyopathy, ANTHRACYCLINE CARDIOTOXICITY, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Multicenter trial, Internal medicine, medicine, MANAGEMENT, Idarubicin, Humans, Online Only Articles, ACUTE LYMPHOBLASTIC-LEUKEMIA, Cardiotoxicity, business.industry, Infant, Newborn, pediatric acute myeloid leukemia, Infant, Surgery, Transplantation, business, 030215 immunology, Follow-Up Studies
Abstract

International audience; Late cardiomyopathy in childhood acute myeloid leukemia survivors: a study from the L.E.A. program Prognosis of pediatric acute myeloid leukemia (AML) has improved significantly over the past two decades with survival rates now approaching 70%. 1 Therapy consists of a limited number of intensive chemotherapy courses mainly based on cytarabine and anthracycline. 2,3 Many pediatric late anthracycline cardiotoxicity studies have concerned heterogeneous diagnostic groups. Moreover, single childhood cancer studies were mainly conducted in acute lym-phoblastic leukemia, whereas the highest doses of anthra-cycline are given in children with AML. 4-6 We report here a prospective multi-centric study of late cardiotoxicity in 185 patients surviving childhood AML. All were treated after 1989 in French clinical trials using intensive chemotherapy alone or chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). L.E.A. (Leucémie Enfant & Adolescent) is a French prospective long-term follow-up program involving all childhood acute leukemia survivors treated in the participating centers since 1980. Details of the programm are provided elsewhere. 7 As of 31 December 2011, 282 childhood AML survivors fulfilled the L.E.A. inclusion criteria and 218 (77.3%) of them agreed to participate. Among these 218, 185 were treated according to one of the 6 multicenter trial protocols ongoing in France after January 1989. All 185 had serial echocardiographic examination as part of their L.E.A. program, and all were included in the present study. All provided written informed consent. Cardiotoxicity was defined by either clinical symptoms of congestive heart failure or by an abnormal echocardiographic left ventricular function. Left ventricular function was considered abnormal when the shortening fraction (SF) was less than 28% or when the left ventricular ejection fraction (LVEF) was less than 55% on 2D echocardiography. 8-10 Cardiotoxicity was classified as late when it started or persisted beyond one year after the completion of first-line treatment. 9 Cumulative anthracycline doses used in each trial are described in the Online Supplementary Table S1, as well as the doxorubicin-equivalent doses using conversion factors of 0.83, 4.0 and 5.0 for daunorubicin, mitoxantrone and idarubicin, respectively. 10,11 Assessment of health status, long-term late effects on health-related quality of life (QoL), and statistical analysis are described in the Online Supplementary Appendix. Characteristics of the study cohort are summarized in Table 1. Median age at the time of AML diagnosis and median follow-up duration to last cardiac evaluation were 6.53 and 9.5 years, respectively. Thirty-seven patients had a history of relapse. Median cumulative anthracycline dose was 372 mg/m² (Online Supplementary Figure S1). Ninety-nine patients were treated by chemotherapy alone, whereas the other 86 patients also received HSCT (57 in first remission, 25 in second remission, and 4 in more advanced disease). Thirty children received total body irradiation (TBI), but only 10 among the 57 transplanted in first remission did so. Median number of echographic evaluations was 3 per patient. Subclinical cardiotoxicity (SCC) was observed in 23 of 185 patients (12.4%) at least once during their follow-up program. Median time from AML diagnosis to SCC detection was 4.40 years. In these 23 patients, the median value of the worst SF was 27% and the median value of the worst LVEF was 52. Only 3 of 23 patients had a worse SF value of less than 25% (2 had 20%; 1 had 24%). Six of 23 received anti-congestive therapy and none had cardiac transplantation. Five of those receiving anti-congestive therapy were still being treated at time of last evaluation, and 4 had more than 28% SF and more than 55% LVEF. Seventeen patients never received treatment: 11 had spontaneous improvement with more than 28% SF and more than 55% LVEF at last evaluation. Finally, at last cardiac evaluation, only 8 patients had an abnormal left ventricular function. Cumulative incidence (CI) of cardiotoxicity, estimated by the Kaplan-Meier method was 16% and 27% at 10 and 15 years, respectively (Figure 1A). CI of anti-conges-tive treatment at the same follow-up times was 5% and 7%. The risk of developing cardiotoxicity depended on a previous history of relapse and on the cumulative anthracy-cline dose. At ten years from diagnosis, CI was 35% versus 11% in patients with or without history of relapse (P=0.02) (Figure 1B). Among 148 patients without any history of relapse, 10-year CI of cardiotoxicity was 14% in 97 patients treated with chemotherapy alone versus 8% in 51 patients who underwent HSCT in first remission (NS, Figure 1C). In transplanted children, the risk was not modified by either a grade 2-4 acute or an extensive chronic graft-versus-host disease. The CI of anti-congestive treatment in these 148 patients who never experienced relapse was 3% at ten and

Published
2015
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7. Household exposure to pesticides and risk of childhood acute leukaemia

Author

Brigitte Nelken, Florence Menegaux, André Baruchel, Brigitte Lescoeur, Yves Bertrand, Denis Hémon, Danièle Sommelet, Guy Leverger, Jacqueline Clavel, Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie pédiatrique, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service pédiatrique d'hématologie, Hospices Civils de Lyon (HCL)-Hôpital Debrousse, Hospices Civils de Lyon (HCL), 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 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), Service pédiatrique d'hématologie-oncologie, Hôpital Jeanne de Flandre [Lille], Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Kaniewski, Nadine

Subjects
Male, Insecticides, Pediculosis, Ethnic origin, 010501 environmental sciences, MESH: Epidemiologic Methods, 01 natural sciences, MESH: Pregnancy, 0302 clinical medicine, Pregnancy, MESH: Child, Epidemiology, MESH: Maternal Exposure, Child, Acute leukemia, Leukemia, MESH: Infant, Newborn, Environmental exposure, Lice Infestations, MESH: Prena, MESH: Infant, 3. Good health, Maternal Exposure, Child, Preschool, Prenatal Exposure Delayed Effects, 030220 oncology & carcinogenesis, Acute Disease, Paternal Exposure, MESH: Acute Disease, Female, Original Article, medicine.medical_specialty, Adolescent, MESH: Environmental Exposure, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Environmental health, MESH: Leukemia, medicine, Humans, MESH: Pesticides, Pesticides, Risk factor, 0105 earth and related environmental sciences, MESH: Adolescent, MESH: Paternal Exposure, MESH: Humans, business.industry, MESH: Child, Preschool, Infant, Newborn, MESH: Lice Infestations, Public Health, Environmental and Occupational Health, Infant, Environmental Exposure, Odds ratio, medicine.disease, MESH: Male, MESH: Insecticides, Surgery, Scalp Dermatoses, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Epidemiologic Methods, business, MESH: Female
Abstract

International audience; OBJECTIVES: To investigate the relation between childhood acute leukaemia and household exposure to pesticides. METHODS: The study included 280 incident cases of acute leukaemia and 288 controls frequency matched on gender, age, hospital, and ethnic origin. The data were obtained from standardised face to face interviews of the mothers with detailed questions on parental occupational history, home and garden insecticide use, and insecticidal treatment of pediculosis. Odds ratios were estimated using unconditional regression models including the stratification variables parental socioeconomic status and housing characteristics. RESULTS: Acute leukaemia was observed to be significantly associated with maternal home insecticide use during pregnancy (OR = 1.8, 95% CI 1.2 to 2.8) and during childhood (OR = 1.7, 95% CI 1.1 to 2.4), with garden insecticide use (OR = 2.4, 95% CI 1.3 to 4.3), and fungicide use (OR = 2.5, 95% CI 1.0 to 6.2) during childhood. Insecticidal shampoo treatment of pediculosis was also associated with childhood acute leukaemia (OR = 1.9, 95% CI 1.2 to 3.3). CONCLUSION: The results reported herein support the hypothesis that various types of insecticide exposure may be a risk factor for childhood acute leukaemia. The observed association with insecticidal shampoo treatment of pediculosis, which has never been investigated before, requires further study.

Published
2006
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8. Maternal coffee and alcohol consumption during pregnancy, parental smoking and risk of childhood acute leukaemia

Author

Christoph Steffen, André Baruchel, Brigitte Lescoeur, Denis Hémon, Stéphanie Bellec, Brigitte Nelken, Jacqueline Clavel, N Philippe, Guy Leverger, Florence Menegaux, Danièle Sommelet, Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie pédiatrique, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), 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 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), Service pédiatrique d'hématologie-oncologie, Hôpital Jeanne de Flandre [Lille], Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Kaniewski, Nadine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Cancer Research, Pediatrics, Maternal smoking, Ethnic origin, Coffee, MESH: Pregnancy, 0302 clinical medicine, Pregnancy, Risk Factors, MESH: Risk Factors, MESH: Child, 030212 general & internal medicine, MESH: Maternal Exposure, Child, Acute leukemia, Leukemia, MESH: Case-Control Studies, MESH: Infant, MESH: Mothers, Alcohol consumption during pregnancy, 3. Good health, Oncology, Maternal Exposure, Child, Preschool, 030220 oncology & carcinogenesis, MESH: Tobacco Smoke Pollution, Female, MESH: Socioeconomic Factors, medicine.medical_specialty, Adolescent, Alcohol Drinking, Childhood leukemia, Mothers, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Leukemia, medicine, Humans, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, Case-control study, Infant, MESH: Coffee, medicine.disease, MESH: Male, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Socioeconomic Factors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Tobacco Smoke Pollution, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, MESH: Alcohol Drinking
Abstract

International audience; INTRODUCTION: We investigated the role of maternal alcohol and coffee drinking and parental smoking on the risk of childhood acute leukemia in a multicenter case-control study. METHODS: The study included 280 incident cases and 288 hospitalized controls, frequency matched with the cases by age, gender and center. Data collection was completed by face-to-face standardized interviews of the case and control mothers. RESULTS: An association with maternal alcohol consumption during pregnancy was observed with acute lymphoid leukemia (ALL) (OR=2.0 [1.4-3.0]) and acute non-lymphoid leukemia (ANLL) (OR=2.6 [1.2-5.8]). Maternal coffee consumption during pregnancy was associated with childhood acute leukemia, ORs increasing in ALL with coffee consumption (OR=1.1 [0.7-1.8], OR=2.4 [1.3-4.7] and OR=3.1 [1.0-9.5], respectively, for < or =3, 4-8 and >8 cups/day). No association with maternal smoking during pregnancy or parental smoking before or after the index child's birth was observed. DISCUSSION: Our results suggest an association with maternal alcohol and coffee drinking during pregnancy and call for further investigations. Besides, the present study does not support the hypothesis of an increase in the risk of childhood leukemia related to parental smoking.

Published
2005
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9. A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee)

Author

Nelken, Brigitte, Cavé, Hélène, Leverger, Guy, Galambrun, Claire, Plat, Genevieve, Schmitt, Claudine, Thomas, Caroline, Vérité, Cecile, Brethon, Benoit, Gandemer, Virginie, Bertrand, Yves, Baruchel, André, Rohrlich, Pierre, Pôle Enfant, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Lille Nord (France), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Pellegrin Tripode, Pediatric Onco-Hematology Unit, CHU Pontchaillou [Rennes], 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 ), Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), 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 d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Direction de la Recherche Clinique du CHRU de Lille, 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 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 ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, and Jonchère, Laurent

Subjects
Male, Salvage Therapy, Adolescent, Dose-Response Relationship, Drug, Maximum Tolerated Dose, Adenine Nucleotides, [SDV]Life Sciences [q-bio], acute lymphoblastic leukemia, phase I, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Dexamethasone, [SDV] Life Sciences [q-bio], Young Adult, resistant disease, Child, Preschool, Antineoplastic Combined Chemotherapy Protocols, Asparaginase, Humans, Female, Arabinonucleosides, Mitoxantrone, Neoplasm Recurrence, Local, Child, Clofarabine, Etoposide
Abstract

International audience; BACKGROUND: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine. PATIENTS AND METHODS: A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2) /d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse. RESULTS: Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2) ), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2) ), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2) . There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation. CONCLUSION: Clofarabine MTD was 32 mg/m(2) /d in this combination which appeared feasible and effective in this population. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc

Published
2014
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10. Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease-guided protocol

Author

Elizabeth Macintyre, Pascale Schneider, Claire Galambrun, Cécile Pochon, Jean-Hugues Dalle, Pierre Bordigoni, Virginie Gandemer, Geneviève Margueritte, Gérard Michel, Patrick Lutz, Claudine Schmitt, Eva de Berranger, Emmanuel Oger, Hélène Cavé, François Demeocq, Marilyne Poirée, Nathalie Grardel, Jean-Michel Cayuela, Francoise Mechinaud, Pierre Rorhlich, Dominique Plantaz, 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 Pharmacologie [Rennes], CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université Paris Diderot - Paris 7 (UPD7), Service de Biochimie Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Laboratoire central d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Children's Cancer Center, The Royal Children's Hospital, Hôpital Civil, Hopital Civil, Service d'hématologie pédiatrique, CHU Clermont-Ferrand, Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service Hématologie Infantile, CHU Grenoble, Unité de Transplantation Médullaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital d'enfants, 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), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Oncology, Male, medicine.medical_specialty, Neoplasm, Residual, Multivariate analysis, Adolescent, medicine.medical_treatment, Hematopoietic stem cell transplantation, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Adjuvants, Immunologic, Immunologic, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Combined Modality Therapy, Humans, Cumulative incidence, Adjuvants, Prospective Studies, Prospective cohort study, Child, Preschool, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Remission Induction, Hematopoietic Stem Cell Transplantation, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Minimal residual disease, 3. Good health, Surgery, Transplantation, body regions, Treatment Outcome, Child, Preschool, 030220 oncology & carcinogenesis, Residual, Lymphoblastic leukaemia, Neoplasm, Female, business, 030215 immunology
Abstract

International audience; Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD \textless10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43*6 vs. 16*7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72*3% of patients with MRD\textless10(-3) and 40*4% of those with MRD ≥10(-3).

Published
2014
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11. Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma

Author

Agata Cieslak, André Baruchel, Elizabeth Macintyre, Céline Callens, Claudine Schmitt, Anne Moreau, Patrick Villarese, Arnaud Petit, Raouf Ben Abdelali, Frederic Baleydier, Veronique Minard-Colin, Etienne Lengliné, Yves Bertrand, Anne Rullier, Vahid Asnafi, Cytokines, hématopoïèse et réponse immune ( CHRI ), 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 de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), CIC - Biotherapie - GHU Ouest APHP ( CIC-BT 502 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], CHU Trousseau [APHP], Laboratoire d'hématologie ( ERL 8254 ), 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 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 ), Department of Immunology, Duke University Medical Center, Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de Mathématiques et Applications ( LMA-Poitiers ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -CHU Saint Louis [APHP], Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Cytokines, hématopoïèse et réponse immune (CHRI), 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 de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), 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)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - 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), Laboratoire de Mathématiques et Applications (LMA-Poitiers), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-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)-CHU Necker - Enfants Malades [AP-HP], 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 Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Male, Cancer Research, F-Box-WD Repeat-Containing Protein 7, MESH : F-Box Proteins, Cell Cycle Proteins, MESH : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, MESH: Calcium-Binding Proteins, MESH : Child, Preschool, medicine.disease_cause, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, MESH: Receptor, Notch1, MESH : Receptors, Antigen, T-Cell, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Cell Cycle Proteins, MESH : Child, MESH: Child, MESH : Calcium-Binding Proteins, MESH : Female, Receptor, Notch1, Prospective cohort study, Child, Sequence Deletion, 0303 health sciences, Mutation, MESH : Prognosis, MESH : Receptor, Notch1, MESH: Receptors, Antigen, T-Cell, MESH : Infant, MESH: Sequence Deletion, Prognosis, MESH: Infant, 3. Good health, MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Female, MESH : Mutation, MESH : Apoptosis Regulatory Proteins, MESH: Mutation, Tumor suppressor gene, Adolescent, T cell, Ubiquitin-Protein Ligases, MESH : Male, Receptors, Antigen, T-Cell, MESH: F-Box Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH : Adolescent, medicine, Humans, 030304 developmental biology, MESH: Adolescent, MESH: Humans, business.industry, MESH: Apoptosis Regulatory Proteins, F-Box Proteins, MESH : Sequence Deletion, Lymphoblastic lymphoma, T-cell receptor, Calcium-Binding Proteins, MESH: Child, Preschool, MESH : Humans, Infant, medicine.disease, Minimal residual disease, MESH: Ubiquitin-Protein Ligases, MESH: Male, Clinical trial, Cancer research, MESH : Ubiquitin-Protein Ligases, business, Apoptosis Regulatory Proteins, MESH: Female
Abstract

Purpose Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/Fmut), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. Patients and Methods Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/Fmut were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRβ, and TCRδ rearrangements. Results N/Fmut were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRγ deletion (ABD) was seen in 7%, all of which were N/Fmut and identified a poor prognosis group (P = .02). On multivariate analysis of N/Fmut, TCRγ ABD, and FLASH deletion, only N/Fmut was an independent factor for good prognosis. Conclusion Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.

Published
2012
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12. Prognosis of ETV6/RUNX1 leukemia relapses

Author

Gandemer, Virginie, Chevret, Sylvie, Petit, Arnaud, Vermylen, Christiane, Leblanc, Thierry, Michel, Gerard, Schmitt, Claudine, Lejars, Odile, Schneider, Pascale, Demeocq, Francois, Bader-Meunier, Brigitte, Bernaudin, Francoise, Perel, Yves, Auclerc, Marie-Francoise, Cayuela, Jean-Michel, Leverger, Guy, Baruchel, Andre, Service de médecine de l'enfant et de l'adolescent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique Hématologique, Clinique Universitaire Saint-Luc, de Duve Institute, UCL, Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Clermont-Ferrand, Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Hôpital intercommunal de Créteil, Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Laboratoire central d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de médecine de l'enfant et de l'adolescent [CHU Rennes], CHU Pontchaillou [Rennes], CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
relapse, hemic and lymphatic diseases, childhood leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, prognosis, ETV6/RUNX1, acute lymphoblastic
Abstract

International audience; Purpose. The prognosis of relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long term follow-up a retrospective study to address the outcome of ETV6/RUNX1-positive leukemia relapses.Design and Method. Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified as low or intermediate risk groups. Median follow-up after relapse was 54.2 months. All but three received a second-line salvage therapy and 16 underwent an allogeneic transplantation.Results. ETV6/RUNX1 greatly impacted on overall survival after relapse (3 year-survival= 64.7 % for positive versus 46.5 % for negative cases) (p= 0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (p=0.04). 81.4 % were late relapses, early combined or isolated extramedullar relapses. The 5-year survival rate of ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.6% when relapse occurred after 36 months (vs 34.9%). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome.Conclusions. We found an excellent outcome for ETV6/RUNX1-positive leukemia relapses occurring over 36 months post-diagnosis. Duration of first complete remission may thus be a guide to define the treatment strategy of ETV6/RUNX1-positive leukemia relapse.

Published
2012
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13. Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol

Author

Gandemer, Virginie, Chevret, Sylvie, Petit, Arnaud, Vermylen, Christiane, Leblanc, Thierry, Michel, Gerard, Schmitt, Claudine, Lejars, Odile, Schneider, Pascale, Demeocq, Francois, Bader-Meunier, Brigitte, Bernaudin, Francoise, Perel, Yves, Auclerc, Marie-Francoise, Cayuela, Jean-Michel, Leverger, Guy, Baruchel, Andre, De Villemeur, Hervé, Service de médecine de l'enfant et de l'adolescent [CHU Rennes], CHU Pontchaillou [Rennes], Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique Hématologique, Clinique Universitaire Saint-Luc, de Duve Institute, UCL, Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Clermont-Ferrand, Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Hôpital intercommunal de Créteil, Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Laboratoire central d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
relapse, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, childhood leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, prognosis, ETV6/RUNX1, acute lymphoblastic
Abstract

International audience; Purpose. The prognosis of relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long term follow-up a retrospective study to address the outcome of ETV6/RUNX1-positive leukemia relapses.Design and Method. Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified as low or intermediate risk groups. Median follow-up after relapse was 54.2 months. All but three received a second-line salvage therapy and 16 underwent an allogeneic transplantation.Results. ETV6/RUNX1 greatly impacted on overall survival after relapse (3 year-survival= 64.7 % for positive versus 46.5 % for negative cases) (p= 0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (p=0.04). 81.4 % were late relapses, early combined or isolated extramedullar relapses. The 5-year survival rate of ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.6% when relapse occurred after 36 months (vs 34.9%). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome.Conclusions. We found an excellent outcome for ETV6/RUNX1-positive leukemia relapses occurring over 36 months post-diagnosis. Duration of first complete remission may thus be a guide to define the treatment strategy of ETV6/RUNX1-positive leukemia relapse.

Published
2012
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14. Childhood leukaemia, polymorphisms of metabolism enzyme genes, and interactions with maternal tobacco, coffee and alcohol consumption during pregnancy

Author

Guy Leverger, Florence Menegaux, Anne Lambilliotte, Philippe Beaune, Danièle Sommelet, André Baruchel, Stéphanie Bellec, Marie-Anne Loriot, Sandra Rebouissou, Catherine Bonaïti-Pellié, Jean Feunteun, Denis Hémon, Jacqueline Clavel, Kamila Kebaili, Brigitte Lescoeur, Kaniewski, Nadine, Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Toxicologie Moleculaire (U490), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-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)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie : Immuno-Hématologie pédiatrique et transplantation de moelle osseuse, Hôpital Debrousse, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie pédiatrique-oncologie, Hôpital Jeanne de Flandre [Lille], 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), Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Toxicologie Moleculaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique épidémiologique et structures des populations humaines ( Inserm U535 ), Epidémiologie, sciences sociales, santé publique ( IFR 69 ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (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 ) -Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (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 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 )

Subjects
Cancer Research, Epidemiology, MESH : Polymorphism, Genetic, MESH : Prenatal Exposure Delayed Effects, Physiology, EPHX1, MESH : Child, Preschool, Coffee, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Res, MESH: Pregnancy, MESH : Child, Pregnancy, Risk Factors, Polymorphism (computer science), MESH: Child, Genotype, Odds Ratio, MESH : Female, Child, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Glutathione Transferase, Genetics, 0303 health sciences, Leukemia, Smoking, MESH : Acute Disease, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH : Adult, MESH: Case-Control Studies, 3. Good health, MESH: Cytochrome P-450 CYP1A1, Oncology, Child, Preschool, Prenatal Exposure Delayed Effects, 030220 oncology & carcinogenesis, Acute Disease, MESH: Acute Disease, Female, Adult, MESH : Case-Control Studies, MESH : Glutathione Transferase, Alcohol Drinking, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, MESH: Prenatal Exposure Delayed Effects, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Leukemia, MESH: Polymorphism, Genetic, Cytochrome P-450 CYP1A1, medicine, Humans, MESH: Res, Allele, Risk factor, 030304 developmental biology, MESH: Glutathione Transferase, Polymorphism, Genetic, MESH: Humans, MESH : Humans, MESH : Leukemia, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, MESH: Coffee, MESH: Adult, Odds ratio, medicine.disease, MESH : Coffee, MESH: Odds Ratio, MESH : Pregnancy, MESH : Alcohol Drinking, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, MESH : Cytochrome P-450 CYP1A1, MESH : Odds Ratio, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female, MESH: Alcohol Drinking, Blood sampling
Abstract

International audience; Metabolic polymorphisms may influence the risk of childhood leukaemia related to maternal tobacco, coffee or alcohol consumption. The data were extracted from a case-control study including 280 cases of acute leukaemia and 288 controls. Blood sampling was obtained for a representative subset of 219 cases and 105 controls. Gene-environment interactions were estimated using both case-control and case-only analyses. The polymorphisms of CYP1A1, GSTM1, GSTP1, GSTT1 and NQO1 were not associated with the risk of leukaemia. The slow EPHX1 allele was negatively associated with childhood leukaemia while an inverse non-significant association was observed with the fast EPHX1 allele. Maternal smoking during pregnancy was not related to leukaemia, but an interaction was observed in the case-only analysis with CYP1A1*2A variant allele (odds ratio (OR) 2.2 [1.0-4.9]) and with GSTM1 deletion (OR 2.3 [1.2-4.4]). Conversely, coffee drinking interacted negatively with NQO1 polymorphism in the case-only analysis (OR 0.6 [0.3-1.2] and 0.4 [0.1-1.0] for light and heavy coffee consumptions, respectively). This study suggests that maternal smoking may be a risk factor for leukaemia in children who carry CYP1A1 or GSTM1 genotypes, which might increase reactive metabolites of polycyclic aromatic hydrocarbons.

Published
2005

15. Incidence of childhood leukaemia and non-Hodgkin's lymphoma in France: National Registry of Childhood Leukaemia and Lymphoma, 1990-1999

Author

Stéphanie Bellec, Brigitte Nelken, Denis Hémon, Guy Leverger, Jacqueline Clavel, Marie-Françoise Auclerc, Etienne Vilmer, C Waterkeyn, André Baruchel, A. Goubin, Anne Auvrignon, Catherine Patte, Danièle Sommelet, Nathalie Philippe, F Perrillat-Menegaux, Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe FRALLE, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Children´s Leukaemia Cooperative Group (CLCG), EORTC, LMB, Institut Gustave Roussy (IGR), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), 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), Service hématologie-oncologie pédiatrique, Hôpital Jeanne de Flandre [Lille], Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Registre National des Hémopathies malignes de l'Enfant (RNHE), Institut de Veille Sanitaire (INVS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kaniewski, Nadine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Cancer Research, Pediatrics, Time Factors, MESH: Registries, Epidemiology, Disease, MESH: Research Support, Non-U.S. Gov't, 0302 clinical medicine, MESH: Lymphoma, Non-Hodgkin, immune system diseases, MESH: Leukemia, Lymphocytic, Acute, hemic and lymphatic diseases, MESH: Child, Registries, 030212 general & internal medicine, MESH: Incidence, Child, education.field_of_study, Leukemia, Incidence, Lymphoma, Non-Hodgkin, Incidence (epidemiology), Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Infant, 3. Good health, Childhood leukaemia, Haematopoiesis, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Female, France, medicine.medical_specialty, Adolescent, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Sex Factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Sex Factors, MESH: Leukemia, medicine, Humans, education, MESH: Adolescent, MESH: Humans, business.industry, MESH: Time Factors, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Infant, medicine.disease, MESH: Male, Non-Hodgkin's lymphoma, Lymphoma, MESH: France, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, National registry, business, MESH: Female, MESH: Child, Prescho
Abstract

International audience; The French National Registry of Childhood Leukaemia and Lymphoma (NRCL) covers the whole French mainland population aged less than 15 years (approximately 11 million children) for all childhood haematopoietic tumours since 1 January 1990, except Hodgkin's disease, which has been registered since 1 January 1999. During the period from 1990 to 1999, 5757 cases of leukaemia, lymphoma and myelodysplastic syndrome were registered in the NRCL, with an average of 2.5 sources per case. The age-standardized incidence rates per million per year were 43.1 for leukaemia (34.3 for acute lymphoblastic leukaemia, 7.1 for acute myeloblastic leukaemia, 0.6 for chronic myeloid leukaemia and 0.5 for chronic myelomonocytic leukaemia), 8.9 for non-Hodgkin's lymphomas and 6.7 for Hodgkin's disease. Down's syndrome was present in 110 cases of acute leukaemia (2.5%) and three cases of non-Hodgkin's lymphoma (0.3%). The incidence of acute lymphoblastic leukaemia showed a typical peak at age 2 years for girls and 3 years for boys. The incidence rates of leukaemia and non-Hodgkin's lymphoma did not show any temporal trends over the 10 year period.

Published
2004

16. Acute childhood leukaemia and environmental exposure to potential sources of benzene and other hydrocarbons; a case-control study

Author

André Baruchel, Anne Lambilliotte, Etienne Vilmer, K Kebaili, Jacqueline Clavel, Danièle Sommelet, C Steffen, Guy Leverger, Denis Hémon, Marie-Françoise Auclerc, Anne Auvrignon, Secretariat, U754, Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service d'hématologie : Immuno-Hématologie pédiatrique et transplantation de moelle osseuse, Hôpital Debrousse, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie pédiatrique-oncologie, Hôpital Jeanne de Flandre [Lille], Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Male, MESH: Benzene, 010501 environmental sciences, 01 natural sciences, 0302 clinical medicine, Residence Characteristics, hemic and lymphatic diseases, MESH: Child, Epidemiology, Odds Ratio, Medicine, hydrocarbons, MESH: Residence Characteristics, MESH: Maternal Exposure, Child, Confounding, MESH: Infant, Newborn, Environmental exposure, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Case-Control Studies, MESH: Infant, MESH: Leukemia, Lymphocytic, Acute, L1, Maternal Exposure, 030220 oncology & carcinogenesis, Child, Preschool, leukaemia, Original Article, Female, epidemiology, France, environment, medicine.medical_specialty, MESH: Environmental Exposure, Occupational medicine, 03 medical and health sciences, Acute lymphocytic leukemia, Environmental health, MESH: Hydrocarbons, Humans, 0105 earth and related environmental sciences, childhood, Pregnancy, MESH: Humans, business.industry, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Case-control study, Infant, Newborn, Infant, Benzene, Odds ratio, Environmental Exposure, medicine.disease, MESH: Male, MESH: Odds Ratio, MESH: France, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female
Abstract

Aim: To analyse the association between potential environmental exposure to hydrocarbons and the risk of acute childhood leukaemia. Methods: A hospital based multicentre case control study, stratified on centre, age, and sex, with 280 leukaemia cases and 285 controls was carried out. Data were collected by a standardised interview of the mothers. Results: No clear association was seen between maternal occupational exposure to hydrocarbons during pregnancy and leukaemia, or between residential traffic density and leukaemia. There was an association between dwellings neighbouring a petrol station or a repair garage during childhood and the risk of childhood leukaemia (OR 4.0, 95% CI 1.5 to 10.3), with a duration trend. The association, which appeared particularly strong for acute non-lymphocytic leukaemia (OR 7.7, 95% CI 1.7 to 34.3), was not altered by adjustment for potential confounding factors. Conclusions: Results showed an association between acute childhood leukaemia and dwellings neighbouring auto repair garages and petrol stations, which are benzene emitting sources. These findings could be due to chance, although the strength of the association and the duration trend are arguments for a causal association.

Published
2004
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17. Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study

Author

Gandemer, Virginie, Auclerc, Marie-Francoise, Perel, Yves, Vannier, Jean-Pierre, Le Gall, Edouard, Demeocq, Francois, Schmitt, Claudine, Piguet, Christophe, Stephan, Jean-Louis, Lejars, Odile, Debre, Marianne, Jonveaux, Philippe, Cayuela, Jean-Michel, Chevret, Sylvie, Leverger, Guy, Baruchel, Andre, Group, Fralle, Hématogoie pédiatrique, Service d'hématologie pédiatrique, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'onco-hématologie pédiatrique, hôpital Sud, Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Clermont-Ferrand, Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie médicale - Spécialités médicales [CHU Limoges], CHU Limoges, CHU Saint-Etienne, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), Service de Cytogénétique, Service de biostatistiques et information médicale [Saint-Louis], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hôpital Sud, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CHRU Tours, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service d'hématologie-immunologie-oncologie pédiatrique, and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP]

Subjects
Male, MESH : Bone Marrow, MESH : Recurrence, MESH : Antineoplastic Combined Chemotherapy Protocols, medicine.medical_treatment, MESH : Pyrimidines, Gastroenterology, Piperazines, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Study Protocol, 0302 clinical medicine, MESH : Child, MESH: Child, Antineoplastic Combined Chemotherapy Protocols, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Asparaginase, Anthracyclines, Child, MESH: Anthracyclines, MESH: Bone Marrow Transplantation, Bone Marrow Transplantation, MESH: Treatment Outcome, MESH : Acute Disease, MESH : Infant, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Leukocyte Count, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, MESH: Infant, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, Vincristine, MESH: Young Adult, Child, Preschool, 030220 oncology & carcinogenesis, Acute Disease, Imatinib Mesylate, MESH: Acute Disease, MESH: Bone Marrow, MESH : Vincristine, medicine.medical_specialty, Asparaginase, MESH : Young Adult, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Adolescent, Genetics, Humans, MESH: Adolescent, MESH: Age Factors, MESH: Humans, MESH : Humans, MESH: Child, Preschool, Infant, MESH : Prednisone, MESH : Bone Marrow Transplantation, Minimal residual disease, Imatinib mesylate, chemistry, MESH: Pyrimidines, MESH : Piperazines, MESH: Cortisone, MESH: Female, MESH: Prednisone, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, MESH: Piperazines, MESH : Child, Preschool, MESH : Cortisone, Leukocyte Count, chemistry.chemical_compound, Bone Marrow, Recurrence, Prednisone, MESH : Female, Age Factors, Treatment Outcome, medicine.anatomical_structure, Benzamides, Female, medicine.drug, Adolescent, MESH : Male, MESH: Vincristine, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, Young Adult, MESH : Anthracyclines, Internal medicine, MESH : Asparaginase, medicine, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, Chemotherapy, business.industry, Imatinib, MESH: Male, Surgery, MESH: Recurrence, Cortisone, Pyrimidines, MESH: Leukocyte Count, MESH : Age Factors, Bone marrow, business, 030215 immunology
Abstract

Background We explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL) in a study of the effect of early features on prognosis in children. Here we report the long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors. Methods Between 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling. Results Complete remission (CR) was observed in 26 children (72%), of which 13 underwent allogeneic bone marrow transplantation (BMT). Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1). Overall five-year disease-free survival (DFS) was 42 ± 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival [EFS]: 57%, overall survival [OS]: 79%), than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27%) (p < 0.005). We also observed a non statistically significant difference (p = 0.14) in outcome between these groups for transplanted patients (5-year DFS: 83 ± 14% and 33 ± 15%, respectively). Conclusion Age, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.

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