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ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.
Elitzur, Sarah; Shiloh, Ruth; Loeffen, Jan L C; Pastorczak, Agata; Takagi, Masatoshi; Bomken, Simon; Baruchel, Andre; Lehrnbecher, Thomas; Tasian, Sarah K; Abla, Oussama; Arad-Cohen, Nira; Astigarraga, Itziar; Ben-Harosh, Miriam; Bodmer, Nicole; Brozou, Triantafyllia; Ceppi, Francesco; Chugaeva, Liliia; Dalla Pozza, Luciano; Ducassou, Stephane; Escherich, Gabriele; Farah, Roula; Gibson, Amber; Hasle, Henrik; Hoveyan, Julieta; Jacoby, Elad; Jazbec, Janez; Junk, Stefanie; Kolenova, Alexandra; Lazic, Jelena; Lo Nigro, Luca; Mahlaoui, Nizar; Miller, Lane; Papadakis, Vassilios; Pecheux, Lucie; Pillon, Marta; Sarouk, Ifat; Stary, Jan; Stiakaki, Eftichia; Strullu, Marion; Tran, Thai Hoa; Ussowicz, Marek; Verdu-Amoros, Jaime; Wakulinska, Anna; Zawitkowska, Joanna; Stoppa-Lyonnet, Dominique; Taylor, A Malcolm; Shiloh, Yosef; Izraeli, Shai; Minard-Colin, Veronique; Schmiegelow, Kjeld.
Afiliación
  • Elitzur S; Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Shiloh R; Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Loeffen JLC; Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel.
  • Pastorczak A; Department of Hemato-Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • Takagi M; Department of Pediatrics, Oncology and Hematology, and Department of Genetic Predisposition to Cancer, Medical University of Lodz, Lodz, Poland.
  • Bomken S; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
  • Baruchel A; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom.
  • Lehrnbecher T; Department of Pediatric Hemato-Immunology, Hôpital Robert Debré, Paris, France.
  • Tasian SK; Division of Hematology, Oncology and Hemostaseology, Department of Pediatrics, Goethe University Frankfurt, Frankfurt/Main, Germany.
  • Abla O; Division of Oncology and Center for Childhood Cancer Research, Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA.
  • Arad-Cohen N; Division of Hematology/Oncology, Hospital For Sick Children, Toronto, ON, Canada.
  • Astigarraga I; Department of Pediatric Hemato-Oncology, Rambam Health Care Campus, Haifa, Israel.
  • Ben-Harosh M; Pediatrics Department, Hospital Universitario Cruces, Osakidetza, Pediatric Oncology Group, Bizkaia Health Research Institute, Pediatric Department, Universidad del País Vasco UPV/EHU, Barakaldo, Spain.
  • Bodmer N; Department of Pediatric Hematology-Oncology, Soroka Medical Center, Beer Sheva, Israel.
  • Brozou T; Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
  • Ceppi F; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
  • Chugaeva L; Division of Pediatrics, Pediatric Hematology-Oncology Unit, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland.
  • Dalla Pozza L; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.
  • Ducassou S; Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, NSW, Australia.
  • Escherich G; Department of Pediatric Hemato-Oncology, CHU Bordeaux, Bordeaux, France.
  • Farah R; Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Gibson A; Department of Pediatrics and Pediatric Hematology/Oncology, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon.
  • Hasle H; Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Hoveyan J; Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Jacoby E; Pediatric Cancer and Blood Disorders Center of Armenia, Yeolyan Hematology and Oncology Center and Immune Oncology Research Institute, Yerevan, Armenia.
  • Jazbec J; Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Junk S; Department of Pediatric Hematology and Oncology, University Children's Hospital, Faculty of Medicine, University of Ljubljan, Ljubljana, Slovenia.
  • Kolenova A; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
  • Lazic J; Department of Pediatric Hematology and Oncology, National Institute of Children's Diseases, Comenius University Children's Hospital, Bratislava, Slovakia.
  • Lo Nigro L; Department of Hematology and Oncology, University Children's Hospital, School of Medicine University of Belgrade, Belgrade, Serbia.
  • Mahlaoui N; Azienda Policlinico, San Marco, Center of Pediatric Hematology Oncology, Catania, Italy.
  • Miller L; Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, French National Reference Center for Primary Immune Deficiencies, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • Papadakis V; Cancers and Blood Disorders Program, Children's Minnesota, Minneapolis, MN.
  • Pecheux L; Department of Pediatric Hematology-Oncology, Agia Sofia Children's Hospital, Athens, Greece.
  • Pillon M; Department of Pediatric Hematology-Oncology, Stollery Children Hospital, University of Alberta, Edmonton, Canada.
  • Sarouk I; Pediatric Hematology, Oncology and Stem Cell Transplant Center, University of Padua, Padua, Italy.
  • Stary J; Pediatric Pulmonology Unit and Ataxia Telangiectasia Center, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
  • Stiakaki E; Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic.
  • Strullu M; Department of Pediatric Hematology-Oncology, University Hospital of Heraklion, Heraklion Crete, Greece.
  • Tran TH; Department of Pediatric Hemato-Immunology, Hôpital Robert Debré, Paris, France.
  • Ussowicz M; Division of Pediatric Hematology Oncology, CHU Sainte Justine, Montreal, QC, Canada.
  • Verdu-Amoros J; Clinical Department of Paediatric Bone Marrow Transplantation, Oncology and Haematology, Wroclaw Medical University, Wroclaw, Poland.
  • Wakulinska A; Department of Pediatric Hematology and Oncology, University Hospital Valencia, INCLIVA Biomedical Research Institute, Valencia, Spain.
  • Zawitkowska J; Department of Oncology, The Children's Memorial Health Institute, Warsaw, Poland.
  • Stoppa-Lyonnet D; Department of Pediatric Hematology, Oncology and Transplantation, Medical University of Lublin, Lublin, Poland.
  • Taylor AM; Department of Genetics, Institut Curie, INSERM U830, and Université Paris Cité, Paris, France.
  • Shiloh Y; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Izraeli S; Department of Human Molecular Genetics and Biochemistry, Tel Aviv University School of Medicine, Tel Aviv, Israel.
  • Minard-Colin V; Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Schmiegelow K; Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
Blood ; 144(11): 1193-1205, 2024 Sep 12.
Article en En | MEDLINE | ID: mdl-38917355
ABSTRACT
ABSTRACT Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia Telangiectasia / Mutación de Línea Germinal / Neoplasias Hematológicas / Proteínas de la Ataxia Telangiectasia Mutada Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia Telangiectasia / Mutación de Línea Germinal / Neoplasias Hematológicas / Proteínas de la Ataxia Telangiectasia Mutada Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos