title: Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study.
abstract: ESSENTIALS: Children with acute lymphoblastic leukemia (ALL) are at risk of thromboembolism (TE). This is a prospective evaluation of the incidence, risk factors and outcomes of TE in 1038 children with ALL. TE occurred in 6.1% of children, with the highest incidence (20.5%) among those aged 15-17 years. A TE-associated case fatality of 6.4% indicates that TE is a severe complication of ALL treatment.
  
  
  CONCLUSIONS
  
  
  
  BACKGROUND
  Thromboembolism (TE) is a major toxicity in children with acute lymphoblastic leukemia (ALL) and may have a negative impact on ALL treatment.
  
  
  OBJECTIVE
  To examine the cumulative incidence, outcomes and risk factors associated with TE in children with leukemia.
  
  
  METHODS
  We prospectively evaluated TE in 1038 Nordic children and adolescents (≥ 1 and < 18 years) diagnosed with ALL during 2008-2013 and treated according to the NOPHO (Nordic Society of Pediatric Hematology and Oncology)-ALL 2008 protocol. The cohort was followed until December 2014. Cox proportional regression was used to compute hazard ratios (HRs).
  
  
  RESULTS
  TE events (n = 63) occurred most frequently in conjunction with asparaginase (ASP) administration (52/63). The cumulative incidence of TE was 6.1% (95% confidence interval [CI], 4.8-7.7). Being aged 15-17 years was associated with an increased risk of TE (adjusted HR of 4.0; 95% CI, 2.1-7.7). We found a TE-associated 30-day case fatality of 6.4% (95% CI, 1.8-15.5) and TE-related truncation of ASP therapy in 36.2% (21/58). Major hemorrhage occurred in 3.5% (2/58) of anticoagulated patients. Minor hemorrhage was reported in two out of 58 patients. No major bleeds occurred in children who received low-molecular-weight heparin.
  
  
  CONCLUSIONS
  Methods to identify children and adolescents who will benefit from thromboprophylaxis during ALL treatment are called for. The truncation of ASP should be avoided. The long-term survival outcomes for ALL patients with TE require close monitoring in the future.
authors.affiliation: Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Tuckuviene
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Ranta
authors.affiliation: Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: B K
authors.initials: BK
authors.lastname: Albertsen
authors.affiliation: Departments of Pediatrics and Coagulation Disorders, University of Lund, University Hospital, Malmö, Sweden.
authors.forename: N G
authors.initials: NG
authors.lastname: Andersson
authors.affiliation: Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: M D
authors.initials: MD
authors.lastname: Bendtsen
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Frisk
authors.affiliation: Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: M W
authors.initials: MW
authors.lastname: Gunnes
authors.affiliation: Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Helgestad
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
authors.forename: M M
authors.initials: MM
authors.lastname: Heyman
authors.affiliation: Children's Hospital, Landspitali University Hospital, Reykjavík, Iceland.
authors.forename: O G
authors.initials: OG
authors.lastname: Jonsson
authors.affiliation: Children's Hospital and Department of Hematology, Cancer Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Mäkipernaa
authors.affiliation: Department of Oncohematology, Tallinn Children's Hospital, Tallinn, Estonia.
authors.forename: K
authors.initials: K
authors.lastname: Pruunsild
authors.affiliation: Departments of Pediatrics and Coagulation Disorders, University of Lund, University Hospital, Malmö, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Tedgård
authors.affiliation: Center for Pediatric Oncology and Hematology, Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania.
authors.forename: S S
authors.initials: SS
authors.lastname: Trakymiene
authors.affiliation: Department of Pediatric Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Ruud
mesh_terms: D000293:Adolescent; D017677:Age Distribution; D000925:Anticoagulants / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects; D001215:Asparaginase / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D004957:Estonia / Q000453:epidemiology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D007223:Infant; D008097:Lithuania / Q000453:epidemiology; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology* / Q000401:mortality; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012537:Scandinavian and Nordic Countries / Q000453:epidemiology; D013923:Thromboembolism / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality / Q000517:prevention & control; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D000970:Antineoplastic Agents; D001215:Asparaginase
keywords: acute lymphoblastic leukemia; asparaginase; children; thromboembolism