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

Author

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

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

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

Published
2021

3. [Invasive fungal infections in immunocompromised children in paediatric haematology: Recommendations for management in SFCE centres]

Author

Fanny, Alby-Laurent, Wadi Abou, Chahla, Benoît, Brethon, Damien, Dupont, Virginie, Gandemer, Gwenaelle, Gueguen, Fanny, Lanternier, Marlène, Pasquet, Michael, Philippe, Claire, Pluchart, and Carine, Domenech

Subjects
Adult, Immunocompromised Host, Mycoses, Hematologic Neoplasms, Humans, Hematology, Child, Invasive Fungal Infections
Abstract

To date, invasive fungal infections (IFIs) are still responsible for a high mortality rate in children managed for haematological malignancy. Although Candida and Aspergillus infections remain in the majority, emerging fungal infections are increasingly common. Children differ from adults in their pathology and treatment, as well as in their prior fungal colonisation and unique pharmacokinetics. Therefore, we propose here specific paediatric management recommendations for IFIs in haematology.We based our recommendations on a review of the literature, including the latest ECIL recommendations, an analysis of practices and a collection of expert opinions.In France, approximately 5% of children treated for haematological malignancy or who have received a bone marrow allograft present an IFI. These IFIs are equally divided between yeast infections (mainly due to Candida albicans) and filamentous infections (mainly aspergillosis) and 16% are IFIs due to emerging fungi, half of which are due to Mucorales. In these recommendations, we recall the diagnostic criteria for proven or probable IFI according to the Donnelly classification, then we propose strategies for screening, diagnosing, evaluating the extension and treating these three types of IFI. We also detail the diagnostic and therapeutic management of chronic disseminated candidiasis. We also discuss prophylactic measures, including environmental measures which are of primary importance in children.

Published
2022

4. Allergies, genetic polymorphisms of Th2 interleukins, and childhood acute lymphoblastic leukemia: The ESTELLE study

Author

Arnaud Petit, Carine Domenech, Marion Strullu, Brigitte Nelken, Jacqueline Clavel, Audrey Bonaventure, Gérard Michel, Ghinaj Chandab, Roula Ajrouche, Geneviève Plat, Equipe 7 : EPICEA - Epidémiologie des cancers de l'enfant et de l'adolescent (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lebanese University [Beirut] (LU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Robert Debré, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), and Bonaventure, Audrey

Subjects
medicine.medical_specialty, Inverse Association, Childhood leukemia, aetiology, Population, Context (language use), Polymorphism, Single Nucleotide, lymphoblastic leukaemia, Th2 Cells, Internal medicine, Hypersensitivity, medicine, Humans, genetics, Medical history, Child, education, Childhood Acute Lymphoblastic Leukemia, gene-gene interaction, education.field_of_study, Interleukin-13, business.industry, Interleukins, case-control studies, Childhood leukaemia, Case-control study, Hematology, Odds ratio, Precursor Cell Lymphoblastic Leukemia-Lymphoma, allergy, medicine.disease, cytokines, gene-environment interaction, Oncology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Pediatrics, Perinatology and Child Health, epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Interleukin-4, business
Abstract

International audience; Context A negative association between a history of allergy and childhood acute lymphoblastic leukaemia (ALL) has been reported in previous studies, but remains debated. This work aimed to investigate this association accounting for genetic polymorphisms of the Th2 pathway cytokines (IL4, IL10, IL13 and IL4-receptor (IL4R)). Methods Analyses were based on the French case-control study ESTELLE (2010-2011). The complete sample included 629 ALL cases and 1,421 population-based controls frequency-matched on age and gender. The child's medical history was collected through standardised maternal interview. Biological samples were collected, and genotyping data were available for 411 cases and 704 controls of European origin. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. Results In the complete sample, a significant inverse association was observed between ALL and reported history of allergic rhinitis or sinusitis (OR=0.65 [0.42-0.98]; p= 0.04), but there was no obvious association with allergies overall. There was an interaction between genetic polymorphisms in IL4 and IL4R (pinteraction=0.003), as well as a gene-environment interaction between IL4R-rs1801275 and a reported history of asthma (IOR=0.23; pint=0.008) and eczema (IOR= 0.47; pint=0.06). We observed no interaction with the candidate polymorphisms in IL4 and IL13. Conclusion These results suggest that the association between allergic symptoms and childhood ALL could be modified by IL4R-rs1801275, and that this variant could also interact with a functional variant in IL4 gene. While they warrant confirmation, these results could help understand the pathological mechanisms under the reported inverse association between allergy and childhood ALL.

Published
2021

5. Teenagers and young adults with a past of allogenic hematopoietic stem cell transplantation are at significant risk of chronic kidney disease

Author

Luciano, da Silva Selistre, Cécile, Renard, Justine, Bacchetta, Marie-Pierre, Goutagny, Julie, Hu, Vandréa, Carla de Souza, Yves, Bertrand, Laurence, Dubourg, and Carine, Domenech

Subjects
Young Adult, Adolescent, Creatinine, Hematopoietic Stem Cell Transplantation, Humans, Renal Insufficiency, Chronic, Child, Kidney, Glomerular Filtration Rate, Retrospective Studies
Abstract

Allogenic hematopoietic stem cell transplantation (aHSCT) remains the treatment of choice for some malignant hemopathies in children, albeit with the risk of long-term consequences, including chronic kidney disease (CKD).In our single tertiary referral center, we retrospectively assessed the long-term renal outcome in a cohort of children and adolescents who had undergone aHSCT for malignant hemopathies between 2003 and 2017. We distinguished glomerular and tubular dysfunctions and assessed the accuracy of the most common formula(s) to estimate glomerular filtration rate (GFR) during standard clinical follow-up.Among the 166 patients who had received aHSCT, 61 underwent kidney functional assessment 1 to 10 years post-transplantation. Twenty-seven patients (44.3%) had a CKD with glomerular impairment, including 20 patients with a GFR 90 mL/min/1.73 mIn conclusion, our study shows that CKD represents an important long-term sequela for children and adolescents who undergo aHSCT for malignant hemopathies, either with glomerular dysfunction or with the more insidious tubular dysfunction which could potentially impact growth. These patients could benefit from specialized long-term nephrology follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.

Published
2021

6. UL23, UL30, and UL5 characterization of HSV1 clinical strains isolated from hematology department patients

Author

Carine Domenech, Thibault Labrunie, Florence Ader, Sophie Ducastelle, F. Morfin, Emilie Frobert, 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 International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Hematology department, Genotype, DNA polymerase, [SDV]Life Sciences [q-bio], DNA Primase, DNA-Directed DNA Polymerase, Herpesvirus 1, Human, medicine.disease_cause, Antiviral Agents, Thymidine Kinase, Viral Proteins, 03 medical and health sciences, Virology, Drug Resistance, Viral, medicine, Humans, Enzyme Inhibitors, Phylogeny, Retrospective Studies, 030304 developmental biology, Pharmacology, 0303 health sciences, Polymorphism, Genetic, biology, 030306 microbiology, DNA Helicases, Antiviral resistance, Herpes Simplex, Hematology, Exodeoxyribonucleases, Herpes simplex virus, Thymidine kinase, Mutation, biology.protein, Female
Abstract

Genotypic diagnosis of HSV drug resistance can be performed routinely in a clinically relevant time. Nevertheless, data about HSV mutations (polymorphism or resistance) is not exhaustive which hinders the interpretation of such tests. The UL23, UL30, and UL5 genes are of greatest interest as these encode, respectively, thymidine kinase, DNA polymerase, and helicase, which, if mutated may affect the effectiveness of acyclovir, foscarnet, cidofovir, and helicase-primase inhibitors. The present study aimed to extensively characterize UL23, UL30, and UL5 genes. A total of 239 clinical HSV1 recovered from patients admitted to the hematology departments of the Lyon teaching hospitals were included in this single-center retrospective study. Drug resistance was evaluated using the neutral red dye-uptake assay, and sequencing using the Sanger method. Additional information on HSV1 natural polymorphism and resistance is now available. Twenty-two amino acid substitutions related to polymorphism were described on UL23 (E43A, L50M, L68R, Q109K, A133V, A136N, S150L, D258N, S263L, P280S, N301S, A316S, M322L, I326V, D330A, D338H, Q342H, T344I, Q349R, V352L, R370W, E371D), and 6 amino acid substitutions on UL30 (G641R, G645D, E649G, G679D, R681L, I966M). Moreover, the UL23 substitution L242P was added to ACV resistance-related mutations. There were 12 substitutions on UL23 (A37S, V70M, S74L, H151N, P154S, P155Q, L159R, E225L, Y248H, Q270R, N303Y, M372I), and 8 on UL5 (L49I, L138V, S173L, A280T, A575V, V600A, A602T, D862N) that remain of unclear significance with regards to drug resistance. The mean (±standard deviation, SD) number of natural polymorphisms in UL23 was 2.53 (±2.55), in UL30 it was 0.83 (±1.02), and in UL5 it was 5.00 (±1.59) There was no association between HSV1 phenotype and the frequency of substitutions. The results reported herein provide valuable new information concerning HSV1 mutations that will assist the interpretation of genotypic assays.

Published
2019

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

Author

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

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

International audience

Published
2021

8. Pediatric randomized trial EORTC CLG 58951: Outcome for adolescent population with acute lymphoblastic leukemia

Author

Yves Bertrand, Pierre-Simon Rohrlich, Laura Olivier-Gougenheim, Hélène Cavé, Barbara De Moerloose, Anne Uyttebroeck, Alina Ferster, Stefan Suciu, Carine Domenech, Chloé Arfeuille, Geneviève Plat, N Sirvent, Hospices Civils de Lyon (HCL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Organization for Research and Treatment of Cancer (EORTC), EORTC, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), CHU Toulouse [Toulouse], Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Universiteit Gent = Ghent University [Belgium] (UGENT), University Hospitals Leuven [Leuven], and Centre Hospitalier Universitaire de Nice (CHU Nice)

Subjects
Male, Cancer Research, Pediatrics, MESH: Remission Induction, MESH: Combined Modality Therapy, Lymphoblastic Leukemia, genetic abnormalities, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Antineoplastic Combined Chemotherapy Protocols, Medicine, Young adult, MESH: Treatment Outcome, education.field_of_study, Remission Induction, Hematopoietic Stem Cell Transplantation, clinical trial, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Combined Modality Therapy, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Maintenance Chemotherapy, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, outcome, Female, medicine.medical_specialty, Asparaginase, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute lymphoblastic leukemia, MESH: Prognosis, Maintenance Chemotherapy, 03 medical and health sciences, Humans, education, MESH: Hematopoietic Stem Cell Transplantation, MESH: Adolescent, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, Cancer, medicine.disease, MESH: Male, Adolescent population, Clinical trial, chemistry, adolescent, business, MESH: Female, 030215 immunology
Abstract

International audience; Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B-lineage and 27 had T-lineage ALL. The 8-year event-free survival (EFS) and OS for the B-cell precursor ALL cases were 72.3% (59.4%-81.7%) and 80.8% (67.4%-89.1%), respectively. For the T-lineage, the 8-year EFS and OS were 57.4% (36.1%-74.0%) and 59.0% (36.1%-76.2%), respectively. "B-other" ALL, defined as BCP-ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents "B-other" genetic abnormalities in ALL is critical to improve the outcome of this population.

Published
2020

9. Trends in bacterial bloodstream infections and resistance in immuno-compromised patients with febrile neutropenia: a retrospective analysis

Author

Cécile Conter, Yves Bertrand, Christine Fuhrmann, Jean-Philippe Rasigade, Abdelkader Behdenna, Carine Domenech, Coralie Raad, and Daniela Cuzzubbo

Subjects
medicine.medical_specialty, Multi drug resistant bacteria, medicine.drug_class, Antibiotics, Bacteremia, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Sepsis, medicine, Humans, 030212 general & internal medicine, Child, Febrile Neutropenia, Retrospective Studies, Severe combined immunodeficiency, biology, Bacteria, business.industry, Incidence (epidemiology), Bacterial Infections, bacterial infections and mycoses, medicine.disease, biology.organism_classification, Anti-Bacterial Agents, Staphylococcus aureus, Pediatrics, Perinatology and Child Health, Cohort, business, human activities, Febrile neutropenia
Abstract

Bacterial infections remain a major cause of morbidity and mortality in immunocompromised children. From the onset of fever, an early administration of broad-spectrum antibiotics is begun; this strategy could induce emergence of multi-drug resistant bacteria (MDR). We describe the incidence and microbiological spectrum, including MDR bacteria of bacterial documented blood-stream infections (BSI) in immunocompromised children. A retrospective, descriptive study was conducted in a tertiary referral centre in France from January 2014 to December 2017. Our cohort included a large scale of patients with febrile neutropenia: haematological and oncological malignancies, haematopoietic stem cell transplantations, severe combined immunodeficiency syndromes. BSI were defined by positive blood culture samples associated with fever. Among 760 febrile neutropenia episodes in 7301 admitted patients, we identified 310 documented BSI with a mean of 7.4 BSI/1000 patient bed days. Only 2.9% BSIs were caused by MDR bacteria, none vancomycin resistant. Coagulase-negative staphylococci were identified in 49.7% BSI and Staphylococcus aureus caused 6.5% infections. Gram-negative bacilli accounted for 21.6% of isolated bacteria, Pseudomonas for 4.8%. The incidence of BSI annually decreased by 0.75% (p = 0.002).Conclusion: With a step-down strategy at 48 h of initial broad-spectrum antibiotic therapy, we reported a low number of MDR bacteria, no deaths related to BSI. What is Known: • Bacterial bloodstream infections are a leading cause of morbidity and mortality in immunocompromised children • Multi-drug resistant bacteria are emerging worldwide. What is New: • Initial broad-spectrum antibiotic therapy with a step-down strategy at 48 h: no deaths related to bloodstream infections with a low number of resistant bacteria. • Parental and nurse stewardship to decrease bloodstream infections incidence with a drop of staphylococcal infections.

Published
2020

10. Is it leukemia, doctor? No, it's scurvy induced by an ARFID!

Author

Sarah, Benezech, Chrystele, Hartmann, Diane, Morfin, Yves, Bertrand, and Carine, Domenech

Subjects
Feeding and Eating Disorders, Male, Avoidant Restrictive Food Intake Disorder, Leukemia, Adolescent, Humans, Scurvy, Diet
Abstract

We report the case of a 14-year-old boy with a completely normal medical and social background (good student and handball practice). A dentist monthly followed this patient for an orthodontic treatment. Facing with symptoms associating purpura, pancytopenia, and limbs pain, the first diagnosis that came to mind to emergency pediatricians was acute leukemia and the patient was addressed to a hematology department. However, additional psychiatry investigations revealed an avoiding restrictive food intake disorder (ARFID) associated with serious vitamin deficiencies (Vitamins B9 and D) and responsible for scurvy, mimicking acute leukemia onset. Strikingly, this young patient has been undergoing a close medical follow-up since infancy because of a selective diet. Since growth, education, and development were normal, the risk of pursuing this unbalanced diet has been neglected and this child was admitted at diagnosis in a life-threatening condition.

Published
2020

11. CD117

Author

Loïc, Maillard, Sandra, Sanfilippo, Carine, Domenech, Nassima, Kasmi, Laurence, Petit, Sébastien, Jacques, Anne-Lise, Delezoide, Fabien, Guimiot, Soria, Eladak, Delphine, Moison, Nour, Nicolas, Virginie, Rouiller-Fabre, Stéphanie, Pozzi-Godin, Benoit, Mennesson, Marie-Laure, Brival, Franck, Letourneur, Thierry, Jaffredo, Christine, Chomienne, and Michèle, Souyri

Subjects
Proto-Oncogene Proteins c-kit, Fetus, Humans, Cell Differentiation, Hematopoietic Stem Cells, Online Only Articles, Cell Proliferation
Published
2019

12. Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia

Author

Noémie Robil, Laurence Petit, Sébastien Jacques, Michèle Souyri, Denis Clay, Pierre de la Grange, Fabien Guimiot, Loïc Maillard, Fabien Guidez, Sandra Sanfilippo, Marika Pla, Jean Soulier, Alix Rousseau, Carine Domenech, Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Hémopathies Myéloïdes : Cellules Souches, Modèles Pré-Cliniques et Recherche Translationnelle (UMR 1131), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Migration et différenciation des cellules souches hématopoiétiques = Migration and differentiation of hematopoietic stem cells (LBD-E06), Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-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)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-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)-Centre National de la Recherche Scientifique (CNRS), Imagerie Cellulaire et Cytométrie de Flux [IBPS] (IBPS-IP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les cellules souches : de leurs niches à leurs applications thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biologie du Développement [IBPS] (LBD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Erythrocytes, Apoptosis, HSC, Biochemistry, Transcriptome, mouse embryonic development, Fanconi anemia, Pregnancy, Human embryogenesis, Fanconi Anemia Complementation Group G Protein, lcsh:QH301-705.5, lcsh:R5-920, Cell Cycle, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Haematopoiesis, Phenotype, Liver, embryonic structures, Female, Stem cell, lcsh:Medicine (General), human embryonic development, placenta, Embryonic Development, Biology, Article, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Fetus, Bone marrow failure, Cell Biology, medicine.disease, Embryo, Mammalian, Hematopoietic Stem Cells, Embryonic stem cell, Mice, Inbred C57BL, 030104 developmental biology, Fanconi Anemia, Gene Ontology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, lcsh:Biology (General), Cancer research, Developmental Biology, DNA Damage, fetal liver
Abstract

Summary Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg−/− mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg−/− embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg−/− FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology., Highlights • Deep HSC defect in FL and Pl very early during Fancg−/− development • Functional and molecular compensation in Fancg−/− FL HSCs at E14.5 • Deep HSC defect also observed during human FA development • E12.5 Fancg−/− FL could represent a good model for studying Fanconi pathology, A deep HSC defect is present very early during Fancg−/− mouse embryonic development, and is also reported for the first time during human Fanconi anemia development. At E14.5, functional and molecular compensation in Fancg−/− FL HSCs help ensure the survival of Fancg−/− embryos. Altogether E12.5 Fancg−/− FL could represent a good model for studying Fanconi pathology.

Published
2018

13. 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

14. Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial

Author

Karima Yakouben, Barbara De Moerloose, Yves Bertrandfor, Nicole Dastugue, Hélène Cavé, Anne Uyttebroeck, Frédéric Millot, Dominique Plantaz, Yves Benoit, Patrick Lutz, Stefan Suciu, Pierre Rohrlich, Françoise Mazingue, Sandrine Girard, Pierre Philippet, Carine Domenech, Nicolas Sirvent, Martine Munzer, Alina Ferster, and Geneviève Plat

Subjects
Male, medicine.medical_specialty, Adolescent, Prednisolone, Gastroenterology, Dexamethasone, Immunophenotyping, law.invention, Randomized controlled trial, Risk Factors, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Child, Survival rate, Childhood Acute Lymphoblastic Leukemia, business.industry, Infant, Newborn, Infant, Induction chemotherapy, Articles, Induction Chemotherapy, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Minimal residual disease, Surgery, Treatment Outcome, Child, Preschool, Toxicity, Female, business, medicine.drug
Abstract

Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

Published
2014

15. Acute lymphoblastic leukemia in the context of RASopathies

Author

Cédric Vignal, Carine Domenech, Christian P. Kratz, Filomena Pierri, Marion Strullu, Hélène Cavé, Francoise Mechinaud, Nathalie Aladjidi, Audrey Contet, Alain Verloes, Aurélie Caye, Valère Cacheux, Jacqueline Clavel, Alice Ferster, Julie Irving, Hémopathies Myéloïdes : Cellules Souches, Modèles Pré-Cliniques et Recherche Translationnelle (UMR 1131), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Service d’oncologie hématologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Registre National des Cancers de l'Enfant - National Registry of Childhood Cancers [Villejuif & CHU Nancy] (RNCE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and 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)

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Adolescent, Genotype, Context (language use), Protein Tyrosine Phosphatase, Non-Receptor Type 11, RASopathy, Acute lymphoblastic leukemia, PTPN11, 03 medical and health sciences, 0302 clinical medicine, Costello syndrome, Internal medicine, Genetics, medicine, Prevalence, Humans, Noonan syndrome, HRAS, SOS1, Child, RASopathies, Genetics (clinical), business.industry, Infant, Newborn, Infant, Neoplasms, Second Primary, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, 3. Good health, Leukemia, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Child, Preschool, Mutation, ras Proteins, SHP2, Female, business, SOS1 Protein
Abstract

International audience; Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients.

Published
2016

16. Impact of a change in protected environment on the occurrence of severe bacterial and fungal infections in children undergoing hematopoietic stem cell transplantation

Author

Clara Libbrecht, Nathalie Bleyzac, Carine Domenech, Anne-Lise Bienvenu, Christine Ploton, Justine Bacchetta, Yves Bertrand, Marie-Pierre Goutagny, and Valérie Mialou

Subjects
Male, medicine.medical_specialty, Infection risk, Isolation (health care), Adolescent, medicine.medical_treatment, Statistical difference, Positive pressure, Graft vs Host Disease, Bacteremia, Hematopoietic stem cell transplantation, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Transplantation, Homologous, Child, Retrospective Studies, business.industry, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, Infant, Newborn, Infant, Hematology, General Medicine, Bacterial Infections, Antibiotic Prophylaxis, medicine.disease, Environment, Controlled, Prognosis, Survival Analysis, Mycoses, 030220 oncology & carcinogenesis, Allogeneic hsct, Child, Preschool, Immunology, Female, business, 030215 immunology
Abstract

BACKGROUND Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure with a high infection risk. Strict isolation of patients is the rule to prevent such condition. OBJECTIVE We compared the occurrence of severe infections (bacteremia and invasive fungal infection, IFI) in children undergoing alloHSCT before and after the move to a new protected unit with decreases in isolation methods. METHODS The study was conducted over a 10-year period. Unit 1 (2002-2007) consisted of laminar airflow rooms where caregivers were required to wear a sterile outfit (gown, gloves, hat, and mask). Unit 2 (2008-2012) included spacious positive air pressure rooms with HEPA filters where only a clean gown and mask were required to be worn. RESULTS Two hundred eighty-six alloHSCTs were performed (144 in Unit 1 and 142 in Unit 2). We reported a total incidence of 4.78 infections/1000 hospital-days including 4.4 episodes of bacteremia and 0.38 episodes of IFI. There was no statistical difference in the incidence of infections: n = 4.98/1000 hospital-days in Unit 1 vs. n = 4.6/1000 in Unit 2 (P = 0.63). CONCLUSION The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life.

Published
2015

17. Improvement in the Outcome of Invasive Aspergillosis in a Pediatric Hematology Department: A 10-Year Review

Author

Jean-Pierre Pracros, Carine Domenech, Stéphane Picot, Yves Bertrand, Anne-Lise Bienvenu, Charline Leick-Courtois, and Nathalie Bleyzac

Subjects
Male, Pediatrics, medicine.medical_specialty, Antifungal Agents, Adolescent, Population, Antineoplastic Agents, Aspergillosis, Immunocompromised Host, medicine, Humans, education, Child, Retrospective Studies, Voriconazole, Invasive Pulmonary Aspergillosis, Acute leukemia, education.field_of_study, Leukemia, business.industry, Mortality rate, Hematopoietic Stem Cell Transplantation, Infant, Hematology, Invasive pulmonary aspergillosis, medicine.disease, Oncology, Child, Preschool, Pediatrics, Perinatology and Child Health, Liposomal amphotericin, Female, Pediatric hematology, business, medicine.drug
Abstract

BACKGROUND Invasive aspergillosis (IA) is associated with a high mortality rate despite the introduction of new antifungal agents. Several therapeutic strategies have been proposed to improve mortality rates in IA, including combination of drugs. METHODS Here, we report the outcome of treatments based on a combination of antifungal agents on IA, including voriconazole and liposomal amphotericin B, in a pediatric population from 2001 to 2010. Our population included children with diverse hematological diseases or with bone marrow transplantation. RESULTS Over a 10-year period, we diagnosed 19 cases (2,8%) of invasive pulmonary aspergillosis with an overall survival rate of 58%. CONCLUSION Compared with the previous study conducted from 1986 to 2000, the overall survival rate (bone marrow transplantation excluded) greatly improved (12.5% to 58%), especially for patients treated for acute leukemia.

Published
2015

18. [Novel conventional therapies in onco-hemathology]

Author

Frédéric, Baleydier, Carine, Domenech, Xavier, Thomas, equipe 14, 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)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Edouard Herriot [CHU - HCL], and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)

Subjects
MESH: Humans, Adenine Nucleotides, Chemistry, Pharmaceutical, MESH: Arabinonucleosides, Antibodies, Monoclonal, MESH: Adenine Nucleotides, MESH: Pyrimidinones, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Purine Nucleosides, Pyrimidinones, MESH: Antibodies, Monoclonal, MESH: Chemistry, Pharmaceutical, Hematologic Neoplasms, hemic and lymphatic diseases, MESH: Molecular Targeted Therapy, Humans, MESH: Antineoplastic Agents, Arabinonucleosides, Molecular Targeted Therapy, MESH: Purine Nucleosides, Clofarabine, MESH: Hematologic Neoplasms
Abstract

International audience; Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.

Published
2011

19. l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial

Author

Carine, Domenech, Xavier, Thomas, Sylvie, Chabaud, Andre, Baruchel, François, Gueyffier, Françoise, Mazingue, Anne, Auvrignon, Selim, Corm, Herve, Dombret, Patrice, Chevallier, Claire, Galambrun, Françoise, Huguet, Faezeh, Legrand, Françoise, Mechinaud, Norbert, Vey, Irène, Philip, David, Liens, Yann, Godfrin, Dominique, Rigal, Yves, Bertrand, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), equipe 14, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Children's Cancer Center, The Royal Children's Hospital, Hematology (IPC-Marseille), Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC), Centre Léon Bérard [Lyon], Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Adult, Male, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Erythrocytes, Adolescent, MESH: Drug Delivery Systems, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Drug Administration Schedule, Drug Administration Schedule, MESH: Dose-Response Relationship, Drug, Young Adult, MESH: Bioreactors, Bioreactors, Drug Delivery Systems, MESH: Child, Asparaginase, Humans, MESH: Asparaginase, Child, MESH: Adolescent, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, Drug Carriers, MESH: Humans, MESH: Middle Aged, Dose-Response Relationship, Drug, MESH: Erythrocytes, MESH: Child, Preschool, Infant, MESH: Adult, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Infant, MESH: Male, MESH: Drug Carriers, MESH: Young Adult, Child, Preschool, MESH: Antineoplastic Agents
Abstract

International audience; l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) .

Published
2011

20. Cryptosporidiosis in Children With Acute Lymphoblastic Leukemia on Maintenance Chemotherapy

Author

Yves Bertrand, Carine Domenech, Meja Rabodonirina, Nathalie Bleyzac, Marie-Pierre Pages, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, medicine.medical_specialty, Adolescent, Cryptosporidium infection, Lymphoblastic Leukemia, [SDV]Life Sciences [q-bio], Cryptosporidiosis, Maintenance Chemotherapy, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, parasitic diseases, medicine, Humans, 030212 general & internal medicine, Maintenance chemotherapy, Antiparasitic Agents, biology, business.industry, Cryptosporidium, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, biology.organism_classification, 3. Good health, Diarrhea, Treatment Outcome, Oncology, Child, Preschool, Pediatrics, Perinatology and Child Health, medicine.symptom, business
Abstract

Cryptosporidium is recognized as a cause of diarrhea associated with a high mortality in immunocompromised patients. We report on 2 pediatric cases of cryptosporidiosis during maintenance chemotherapy of acute lymphoblastic leukemia. The patients presented severe diarrheas, 1 of them was complicated by a cholangitis. Withdrawal of immunosuppressive treatments and adjunction of an adequate antiparasitic treatment cured the Cryptosporidium infection in both cases.

Published
2011

21. Indirubin derivatives inhibit malignant lymphoid cell proliferation

Author

Régine Catallo, Valérie Mialou, Wei Wen Chien, Martine Ffrench, Cédric Badiou, Amel Chebel, Isabelle Tigaud, Carine Domenech, and Sandrine Kagialis-Girard

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Cancer Research, Indoles, Time Factors, Cell Survival, Blotting, Western, Apoptosis, Cell Cycle Proteins, Jurkat cells, Cell Line, chemistry.chemical_compound, Jurkat Cells, Cyclin-dependent kinase, Cell Line, Tumor, Cyclin E, Oximes, Autophagy, Humans, Lymphocytes, Cytotoxicity, Cell Proliferation, Antibiotics, Antineoplastic, biology, Dose-Response Relationship, Drug, Cell growth, Cell Cycle, Intracellular Signaling Peptides and Proteins, Hematology, Cyclin-Dependent Kinase 6, Cell cycle, Aryl hydrocarbon receptor, Flow Cytometry, Oncology, Biochemistry, chemistry, Cell culture, biology.protein, Cancer research, Indirubin, Cyclin-Dependent Kinase Inhibitor p27
Abstract

Indirubin-3'-monoxime (IO) is a derivative of indirubin, an active compound of a traditional Chinese medicinal recipe used to treat various inflammatory and malignant diseases. The main in vitro targets of IO (i.e. cyclin dependent kinases, glycogen synthase kinase-3beta, Stat 3 and Aryl hydrocarbon receptor) are regulators of lymphocyte activation. We investigated the interest of IO and its derivative 6-bromo-indirubin-3'oxime (6BIO) for inhibiting the growth of malignant lymphoid cells. IO (1-20 microM) induced cell cycle inhibition and cell death in malignant B- (IM9, Reh6) and T- (Jurkat, CEM-T) lymphoid cell lines depending to cell type, doses, and duration of treatment. IO and 6BIO (10 microM) treatment for 24 and 48 h were compared: 6BIO treatment resulted in a stronger cytotoxicity and more profound inhibition of cell proliferation. Taken together, these results showed that IO and, moreover, its derivative 6BIO may be potent antiproliferative agents in malignant lymphoid cells.

Published
2009

22. First isolated extramedullary relapse in children with B-cell precursor acute lymphoblastic leukaemia: results of the Cooprall-97 study

Author

Carine Domenech, Pierre Bordigoni, Marc Puraveau, André Baruchel, Guy Leverger, Emmanuel Plouvier, Gérard Michel, Yves Benoit, Yves Bertrand, Mariette Mercier, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Saint-Jacques, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatric Hematology/Oncology, Ghent University Hospital, 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, 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), Conception et Test de Systèmes MICroélectroniques (SysMIC), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies ( FEMTO-ST ), Université de Technologie de Belfort-Montbeliard ( UTBM ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Conception et Test de Systèmes MICroélectroniques ( SysMIC ), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier ( LIRMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Cancer Research, MESH: Combined Modality Therapy, MESH : Antineoplastic Combined Chemotherapy Protocols, medicine.medical_treatment, MESH : Child, Preschool, MESH : Central Nervous System Neoplasms, Gastroenterology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Central Nervous System Neoplasms, Central Nervous System Neoplasms, 0302 clinical medicine, MESH : Child, MESH: Child, Antineoplastic Combined Chemotherapy Protocols, MESH : Female, Young adult, Age of Onset, Child, MESH: Testicular Neoplasms, MESH: Treatment Outcome, Ovarian Neoplasms, MESH : Neoplasm Recurrence, Local, MESH : Infant, Combined Modality Therapy, MESH: Infant, 3. Good health, MESH : Age of Onset, MESH: Ovarian Neoplasms, MESH: Antineoplastic Combined Chemotherapy Protocols, medicine.anatomical_structure, Treatment Outcome, Oncology, MESH: Young Adult, 030220 oncology & carcinogenesis, Child, Preschool, MESH: Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, MESH : Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, MESH : Disease-Free Survival, Female, MESH: Stem Cell Transplantation, MESH: Neoplasm Recurrence, Local, medicine.medical_specialty, Adolescent, MESH : Male, MESH: Age of Onset, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, Disease-Free Survival, MESH : Stem Cell Transplantation, 03 medical and health sciences, Young Adult, Testicular Neoplasms, Internal medicine, Acute lymphocytic leukemia, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, MESH : Adolescent, medicine, Humans, MESH : Testicular Neoplasms, B cell, MESH: Adolescent, Chemotherapy, MESH: Humans, business.industry, MESH : Ovarian Neoplasms, MESH : Humans, MESH: Child, Preschool, Cancer, Infant, medicine.disease, MESH: Male, Surgery, Radiation therapy, El Niño, MESH: Disease-Free Survival, Age of onset, Neoplasm Recurrence, Local, business, MESH : Combined Modality Therapy, MESH: Female, 030215 immunology, Stem Cell Transplantation
Abstract

International audience; We report on the efficiency of treatment of first isolated extramedullary relapse of B-cell precursor acute lymphoblastic leukaemia. Sixty-eight children and adolescents were included in the trial COPRALL-97. Stratification criteria were time to relapse: first complete remission duration of less than 24 months for group G3A (n=35), relapse beyond 24 months for group G3B (n=33). Treatment consisted of risk-adapted alternating short course multiagent systemic and intrathecal chemotherapy and irradiation (18Gy). Event free survival (EFS) and overall survival (OS) for all registered patients at 6 years were 43% and 55%, respectively. EFS at 4 years for patients of group G3A and G3B were, respectively, 31% and 61% (p=0.0071) while OS at 4 years were, respectively, 40% and 76% (p=0.065). Our analyses highlighted two independent risks factors predictive of decreased EFS: early relapse and age at the initial diagnosis above 6 years. Early central nervous system relapses have a bad prognosis, and new therapeutic strategies are needed.

Published
2008

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