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ATM germline 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, André; 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, Stéphane; Escherich, Gabriele; Farah, Roula; Gibson, Amber; Hasle, Henrik; Hoveyan, Julieta; Jacoby, Elad; Jazbec, Janez; Junk, Stefanie Verena; Kolenova, Alexandra; Lazic, Jelena; Lo Nigro, Luca; Mahlaoui, Nizar; Miller, Lane H; Papadakis, Vassilios; Pecheux, Lucie; Pillon, Marta; Sarouk, Ifat; Stary, Jan; Stiakaki, Eftichia; Strullu, Marion; Tran, Thai Hoa; Ussowicz, Marek; Verdu-Amorós, Jaime; Wakuliñska, Anna Zofia; Zawitkowska, Joanna; Stoppa-Lyonnet, Dominique; Taylor, Alexander Malcolm; Shiloh, Yosef; Izraeli, Shai; Minard-Colin, Véronique; Schmiegelow, Kjeld.
Afiliación
  • Elitzur S; Schneider Children's Medical Center, Petah Tikva, Israel.
  • Shiloh R; Schneider Children's Medical Center, Petach Tikva, Israel.
  • Loeffen JLC; Princess Maxima Centre for Pediatric Oncology, Utrecht, Netherlands.
  • Pastorczak A; Medical University of Lodz, Lodz, Poland.
  • Takagi M; Tokyo Medical and Dental University, Tokyo, Japan.
  • Bomken S; Newcastle University, Newcastle Upon Tyne, United Kingdom.
  • Baruchel A; Hôpital Robert Debré (AP-HP) and Université de Paris, Paris, France.
  • Lehrnbecher T; University of Frankfurt, Frankfurt, Germany.
  • Tasian SK; Children's Hospital of Philadelphia & University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States.
  • Abla O; Hospital for Sick Children, Toronto, Ontario, Canada.
  • Arad-Cohen N; Rambam Medical Center, Haifa, Israel.
  • Astigarraga I; Hospital Universitario Cruces, Barakaldo, Spain.
  • Ben-Harosh M; Soroka Medical Center, Beer_Sheva, Israel.
  • Bodmer N; University Childrens Hospital Zürich, Zûrich, Switzerland.
  • Brozou T; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Duesseldorf, Düsseldorf, Germany.
  • Ceppi F; Lausanne University Hospital, Lausanne, Switzerland.
  • Chugaeva L; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, Moscow, Russian Federation.
  • Dalla-Pozza L; The Cancer Centre for Children, Children's Hospital at Westmead, Westmead, Australia.
  • Ducassou S; CHU Bordeaux, Bordeaux, France.
  • Escherich G; University hospital Hamburg Eppendorf, Hamburg, Germany.
  • Farah R; Lebanese American University Medical Center-Rizk Hospital, Beirut, Lebanon.
  • Gibson A; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
  • Hasle H; Aarhus University Hospital, Aarhus, Denmark.
  • Hoveyan J; Pediatric Cancer and Blood Disorders Center of Armenia, Yeolyan Hematology and Oncology Center and Immune Oncology Research Institute, Armenia, Yerevan, Armenia.
  • Jacoby E; Sheba Medical Center, Tel Hashomer, Israel.
  • Jazbec J; University Medical Center, Children's Hospital, Ljubljana, Slovenia.
  • Junk SV; Heinrich Heine University Düsseldorf, Medical Faculty, Duesseldorf, Germany.
  • Kolenova A; University Childrens´Hospital, Bratislava,, Bratislava, Slovakia.
  • Lazic J; University Children's Hospital, School of Medicine University of Belgrade, Belgrade, Serbia.
  • Lo Nigro L; Azienda Policlinico - San Marco Catania, Catania, Italy.
  • Mahlaoui N; Necker Enfants Malades University Hospital, 75015, France.
  • Miller LH; Children's Minnesota, Minneapolis, Minnesota, United States.
  • Papadakis V; M-arianna V Vardinoyannis- ELPIDA Oncology Unit, Agia Sofia Children's Hospital, Athens, Greece.
  • Pecheux L; Stollery Children Hospital, University of Alberta, Edmonton, Canada.
  • Pillon M; University of Padova, Padova, Italy, Padova, Italy.
  • Sarouk I; Pediatric Pulmonology Unit and Ataxia Telangiectasia Center, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gran, Israel.
  • Stary J; Charles University and University Hospital Motol.
  • Stiakaki E; University Hospital of Heraklion, Heraklion, Greece.
  • Strullu M; AP-HP - Hopital Robert Debré, Paris, France.
  • Tran TH; CHU Sainte-Justine, Montreal, Quebec, Canada.
  • Ussowicz M; Wroclaw Medical University, Wroclaw, Poland.
  • Verdu-Amorós J; Hospital Clínico Universitario de Valencia, valencia, Spain.
  • Wakuliñska AZ; Children's Memorial Health Institute, Warsaw, Poland.
  • Zawitkowska J; Medical University of Lublin, Lublin, Poland.
  • Stoppa-Lyonnet D; Institut Curie, Paris, France.
  • Taylor AM; University of Birmingham, Birmingham, United Kingdom.
  • Shiloh Y; Tel Aviv University School of Medicine, Tel Aviv, Israel.
  • Izraeli S; Schneider Children's Medical Center of Israel, Petach Tiqva, Israel.
  • Minard-Colin V; Gustave Roussy, Villejuif, France.
  • Schmiegelow K; Rigshospitalet University Hospital, Copenhagen, Denmark.
Blood ; 2024 Jun 25.
Article en En | MEDLINE | ID: mdl-38917355
ABSTRACT
Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order 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 eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% 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). Germline 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 (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Israel

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Israel