<i>ATM</i> germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies-Reference-Cited by-同舟云学术

ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies

Published:2024-09-12 Issue:11 Volume:144 Page:1193-1205
ISSN:0006-4971
Container-title:Blood
language:en
Short-container-title:

Author:

Elitzur Sarah¹^ORCID,Shiloh Ruth¹²,Loeffen Jan L. C.³,Pastorczak Agata⁴,Takagi Masatoshi⁵^ORCID,Bomken Simon⁶^ORCID,Baruchel Andre⁷,Lehrnbecher Thomas⁸,Tasian Sarah K.⁹^ORCID,Abla Oussama¹⁰,Arad-Cohen Nira¹¹,Astigarraga Itziar¹²,Ben-Harosh Miriam¹³^ORCID,Bodmer Nicole¹⁴,Brozou Triantafyllia¹⁵,Ceppi Francesco¹⁶,Chugaeva Liliia¹⁷^ORCID,Dalla Pozza Luciano¹⁸,Ducassou Stephane¹⁹,Escherich Gabriele²⁰,Farah Roula²¹^ORCID,Gibson Amber²²^ORCID,Hasle Henrik²³^ORCID,Hoveyan Julieta²⁴^ORCID,Jacoby Elad²⁵^ORCID,Jazbec Janez²⁶,Junk Stefanie¹⁵^ORCID,Kolenova Alexandra²⁷,Lazic Jelena²⁸^ORCID,Lo Nigro Luca²⁹^ORCID,Mahlaoui Nizar³⁰,Miller Lane³¹,Papadakis Vassilios³²^ORCID,Pecheux Lucie³³,Pillon Marta³⁴,Sarouk Ifat³⁵,Stary Jan³⁶^ORCID,Stiakaki Eftichia³⁷^ORCID,Strullu Marion⁷,Tran Thai Hoa³⁸^ORCID,Ussowicz Marek³⁹,Verdu-Amoros Jaime⁴⁰,Wakulinska Anna⁴¹,Zawitkowska Joanna⁴²^ORCID,Stoppa-Lyonnet Dominique⁴³^ORCID,Taylor A. Malcolm⁴⁴^ORCID,Shiloh Yosef⁴⁵,Izraeli Shai¹^ORCID,Minard-Colin Veronique⁴⁶^ORCID,Schmiegelow Kjeld⁴⁷,Nirel Ronit⁴⁸,Attarbaschi Andishe⁴⁹⁵⁰^ORCID,Borkhardt Arndt¹⁵^ORCID

Affiliation:

1. 1Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2. 2Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel

3. 3Department of Hemato-Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

4. 4Department of Pediatrics, Oncology and Hematology, and Department of Genetic Predisposition to Cancer, Medical University of Lodz, Lodz, Poland

5. 5Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan

6. 6Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom

7. 7Department of Pediatric Hemato-Immunology, Hôpital Robert Debré, Paris, France

8. 8Division of Hematology, Oncology and Hemostaseology, Department of Pediatrics, Goethe University Frankfurt, Frankfurt/Main, Germany

9. 9Division 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

10. 10Division of Hematology/Oncology, Hospital For Sick Children, Toronto, ON, Canada

11. 11Department of Pediatric Hemato-Oncology, Rambam Health Care Campus, Haifa, Israel

12. 12Pediatrics Department, Hospital Universitario Cruces, Osakidetza, Pediatric Oncology Group, Bizkaia Health Research Institute, Pediatric Department, Universidad del País Vasco UPV/EHU, Barakaldo, Spain

13. 13Department of Pediatric Hematology-Oncology, Soroka Medical Center, Beer Sheva, Israel

14. 14Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland

15. 15Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany

16. 16Division of Pediatrics, Pediatric Hematology-Oncology Unit, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland

17. 17Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

18. 18Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, NSW, Australia

19. 19Department of Pediatric Hemato-Oncology, CHU Bordeaux, Bordeaux, France

20. 20Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

21. 21Department of Pediatrics and Pediatric Hematology/Oncology, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon

22. 22Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX

23. 23Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

24. 24Pediatric Cancer and Blood Disorders Center of Armenia, Yeolyan Hematology and Oncology Center and Immune Oncology Research Institute, Yerevan, Armenia

25. 25Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

26. 26Department of Pediatric Hematology and Oncology, University Children's Hospital, Faculty of Medicine, University of Ljubljan, Ljubljana, Slovenia

27. 27Department of Pediatric Hematology and Oncology, National Institute of Children's Diseases, Comenius University Children’s Hospital, Bratislava, Slovakia

28. 28Department of Hematology and Oncology, University Children's Hospital, School of Medicine University of Belgrade, Belgrade, Serbia

29. 29Azienda Policlinico, San Marco, Center of Pediatric Hematology Oncology, Catania, Italy

30. 30Immuno-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

31. 31Cancers and Blood Disorders Program, Children's Minnesota, Minneapolis, MN

32. 32Department of Pediatric Hematology-Oncology, Agia Sofia Children's Hospital, Athens, Greece

33. 33Department of Pediatric Hematology-Oncology, Stollery Children Hospital, University of Alberta, Edmonton, Canada

34. 34Pediatric Hematology, Oncology and Stem Cell Transplant Center, University of Padua, Padua, Italy

35. 35Pediatric Pulmonology Unit and Ataxia Telangiectasia Center, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel

36. 36Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic

37. 37Department of Pediatric Hematology-Oncology, University Hospital of Heraklion, Heraklion Crete, Greece

38. 38Division of Pediatric Hematology Oncology, CHU Sainte Justine, Montreal, QC, Canada

39. 39Clinical Department of Paediatric Bone Marrow Transplantation, Oncology and Haematology, Wroclaw Medical University, Wroclaw, Poland

40. 40Department of Pediatric Hematology and Oncology, University Hospital Valencia, INCLIVA Biomedical Research Institute, Valencia, Spain

41. 41Department of Oncology, The Children's Memorial Health Institute, Warsaw, Poland

42. 42Department of Pediatric Hematology, Oncology and Transplantation, Medical University of Lublin, Lublin, Poland

43. 43Department of Genetics, Institut Curie, INSERM U830, and Université Paris Cité, Paris, France

44. 44Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom

45. 45Department of Human Molecular Genetics and Biochemistry, Tel Aviv University School of Medicine, Tel Aviv, Israel

46. 46Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France

47. 47Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark

48. 48Department of Statistics and Data Science, Hebrew University, Jerusalem, Israel

49. 49Department of Pediatric Hematology and Oncology, St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria

50. 50St Anna Children's Cancer Research Institute, Vienna, Austria

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.

Publisher

American Society of Hematology

Link

https://ashpublications.org/blood/article-pdf/144/11/1193/2241569/blood_bld-2024-024283-main.pdf

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