ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies
Language English Country United States Media print
Document type Journal Article, Multicenter Study, Observational Study, Research Support, Non-U.S. Gov't
PubMed
38917355
DOI
10.1182/blood.2024024283
PII: 516719
Knihovny.cz E-resources
- MeSH
- Ataxia Telangiectasia Mutated Proteins * genetics MeSH
- Child MeSH
- Adult MeSH
- Hematologic Neoplasms * genetics mortality MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Child, Preschool MeSH
- Ataxia Telangiectasia * genetics complications mortality MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ATM protein, human MeSH Browser
- Ataxia Telangiectasia Mutated Proteins * MeSH
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.
Azienda Policlinico San Marco Center of Pediatric Hematology Oncology Catania Italy
Cancer Centre for Children The Children's Hospital at Westmead Westmead NSW Australia
Cancers and Blood Disorders Program Children's Minnesota Minneapolis MN
Department of Genetics Institut Curie INSERM U830 and Université Paris Cité Paris France
Department of Hemato Oncology Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands
Department of Oncology The Children's Memorial Health Institute Warsaw Poland
Department of Oncology University Children's Hospital Zurich Zurich Switzerland
Department of Pediatric Hemato Immunology Hôpital Robert Debré Paris France
Department of Pediatric Hemato Oncology CHU Bordeaux Bordeaux France
Department of Pediatric Hemato Oncology Rambam Health Care Campus Haifa Israel
Department of Pediatric Hematology Oncology Agia Sofia Children's Hospital Athens Greece
Department of Pediatric Hematology Oncology Soroka Medical Center Beer Sheva Israel
Department of Pediatric Hematology Oncology University Hospital of Heraklion Heraklion Crete Greece
Department of Pediatrics and Adolescent Medicine Aarhus University Hospital Aarhus Denmark
Department of Pediatrics and Developmental Biology Tokyo Medical and Dental University Tokyo Japan
Department of Pediatrics The University of Texas MD Anderson Cancer Center Houston TX
Department of Statistics and Data Science Hebrew University Jerusalem Israel
Division of Hematology Oncology Hospital For Sick Children Toronto ON Canada
Division of Pediatric Hematology Oncology CHU Sainte Justine Montreal QC Canada
Felsenstein Medical Research Center Faculty of Medicine Tel Aviv University Petah Tikva Israel
Institute of Cancer and Genomic Sciences University of Birmingham Birmingham United Kingdom
Pediatric Hematology Oncology and Stem Cell Transplant Center University of Padua Padua Italy
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