Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study

Kirsten Brunsvig Jarvis; Marissa LeBlanc; Morten Tulstrup; Rikke Linnemann Nielsen; Birgitte Klug Albertsen; Ramneek Gupta; Pasi Huttunen; Ólafur Gisli Jónsson; Cecilie Utke Rank; Susanna Ranta; Ellen Ruud; Kadri Saks; Sonata Saulyte Trakymiene; Ruta Tuckuviene; Kjeld Schmiegelow

doi:10.1016/j.thromres.2019.11.002

Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study

Thromb Res. 2019 Dec:184:92-98. doi: 10.1016/j.thromres.2019.11.002. Epub 2019 Nov 7.

Authors

Affiliations

¹ Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Postbok 4950, Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072, Blindern, 0316 Oslo, Norway. Electronic address: kirjar@ous-hf.no.
² Oslo Center for Biostatistics and Epidemiology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway.
³ Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark.
⁴ Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark; Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, 380 Huaibeizhuang, Huairou district, Beijing, China.
⁵ Children and Adolescent Health, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark.
⁶ Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark.
⁷ Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, New Children's Hospital, Helsinki University Hospital, Stenbäckinkatu 9, 00290 Helsinki, Finland.
⁸ Children's Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Hringbraut 101, 101 Reykjavik, Iceland.
⁹ Department of hematology, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Pediatric Oncology Research Laboratory, Rigshospitalet, University of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark.
¹⁰ Department of Women's and Children's Health, Karolinska University Hospital, Eugeniavägen 3, 171 76 Solna, Sweden; Childhood Cancer Research Unit, Women's and Children's Health, Karolinska Insitutet, Solnavägen 1, 171 77 Solna, Sweden.
¹¹ Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Postbok 4950, Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072, Blindern, 0316 Oslo, Norway.
¹² Department of Hematology and Oncology, Tallinn Children's Hospital, 13419 Tallinn, Estonia.
¹³ Center for Pediatric Oncology and Hematology, Children's Hospital, Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius 08410, Lithuania.
¹⁴ Department of Pediatrics, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark.
¹⁵ Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Nørregade 10, 1165 Copenhagen, Denmark.

PMID: 31715544
DOI: 10.1016/j.thromres.2019.11.002

Abstract

Introduction: Thromboembolism is a serious toxicity of acute lymphoblastic leukemia treatment, and contributes to substantial morbidity and mortality. Several single nucleotide polymorphisms have been associated with thromboembolism in the general population; however, their impact in patients with acute lymphoblastic leukemia, particularly in children, remains uncertain.

Materials and methods: We collected constitutional DNA and prospectively registered thromboembolic events in 1252 patients, 1-45 years, with acute lymphoblastic leukemia included in the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol in the Nordic and Baltic countries (7/2008-7/2016). Based on previously published data and a priori power calculations, we selected four single nucleotide polymorphisms: F5 rs6025, F11 rs2036914, FGG rs2066865, and ABO rs8176719.

Results: The 2.5 year cumulative incidence of thromboembolism was 7.1% (95% confidence interval (CI) 5.6-8.5). F11 rs2036914 was associated with thromboembolism (hazard ratio (HR) 1.52, 95%CI 1.11-2.07) and there was a borderline significant association for FGG rs2066865 (HR 1.37, 95%CI 0.99-1.91), but no association for ABO rs8176719 or F5 rs6025 in multiple cox regression. A genetic risk score based on F11 rs2036914 and FGG rs2066865 was associated with thromboembolism (HR 1.45 per risk allele, 95%CI 1.15-1.81), the association was strongest in adolescents 10.0-17.9 years (HR 1.64).

Conclusion: If validated, a F11 rs2036914/FGG rs2066865 risk prediction model should be tested as a stratification tool for prevention of thromboembolism in patients with acute lymphoblastic leukemia.

Keywords: Acute lymphoblastic leukemia; Single nucleotide polymorphisms; Thromboembolism.

MeSH terms

Adolescent
Adult
Child
Child, Preschool
Female
Genetic Predisposition to Disease
Humans
Infant
Infant, Newborn
Male
Middle Aged
Polymorphism, Single Nucleotide / genetics*
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Prospective Studies
Risk Factors
Venous Thromboembolism / genetics*
Young Adult