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Haematologica. 2019 Apr;104(4):756-765. doi: 10.3324/haematol.2018.194175. Epub 2018 Sep 27.

THROMBOTECT - a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents.

Author information

1
Children's Hospital of Eastern Switzerland, Hematology and Oncology Department, St. Gallen, Switzerland jeanette.greiner@kispisg.ch.
2
Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
3
Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany.
4
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - Faculty of Medicine, University of Freiburg, Germany.
5
Department of Pediatrics, Zentrum für Kinder- und Jugendmedizin, Klinikum Oldenburg GmbH, Germany.
6
Institute for Clinical Transfusion Medicine and Children's Hospital, Klinikum Braunschweig GmbH, Germany.
7
Department of Pediatric Hematology and Oncology, Children's Hospital, University of Cologne, Germany.
8
Department of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland.
9
Hospital for Children and Adolescents, Klinikum Augsburg, Germany.
10
Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany.
11
Pediatric Oncology, Otto von Guericke University Children's Hospital, Magdeburg, Germany.
12
University Hospital Schleswig-Holstein, Department of Pediatrics, University of Lübeck, Germany.
13
HELIOS Children's Hospital GmbH, Erfurt, Germany.
14
Department of Oncology/Hematology, Children's Hospital, Cantonal Hospital Lucerne, Switzerland.
15
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Germany.
16
Center for Laboratory Medicine and Hemostasis and Hemophilia Center, St. Gallen, Switzerland.

Abstract

Thromboembolism is a serious complication of induction therapy for childhood acute lymphoblastic leukemia. We prospectively compared the efficacy and safety of antithrombotic interventions in the consecutive leukemia trials ALL-BFM 2000 and AIEOP-BFM ALL 2009. Patients with newly diagnosed acute lymphoblastic leukemia (n=949, age 1 to 18 years) were randomized to receive low-dose unfractionated heparin, prophylactic low molecular weight heparin (enoxaparin) or activity-adapted antithrombin throughout induction therapy. The primary objective of the study was to determine whether enoxaparin or antithrombin reduces the incidence of thromboembolism as compared to unfractionated heparin. The principal safety outcome was hemorrhage; leukemia outcome was a secondary endpoint. Thromboembolism occurred in 42 patients (4.4%). Patients assigned to unfractionated heparin had a higher risk of thromboembolism (8.0%) compared with those randomized to enoxaparin (3.5%; P=0.011) or antithrombin (1.9%; P<0.001). The proportion of patients who refused antithrombotic treatment as allocated was 3% in the unfractionated heparin or antithrombin arms, and 33% in the enoxaparin arm. Major hemorrhage occurred in eight patients (no differences between the groups). The 5-year event-free survival was 80.9±2.2% among patients assigned to antithrombin compared to 85.9±2.0% in the unfractionated heparin group (P=0.06), and 86.2±2.0% in the enoxaparin group (P=0.10). In conclusion, prophylactic use of antithrombin or enoxaparin significantly reduced thromboembolism. Despite the considerable number of patients rejecting the assigned treatment with subcutaneous injections, the result remains unambiguous. Thromboprophylaxis - for the present time primarily with enoxaparin - can be recommended for children and adolescents with acute lymphoblastic leukemia during induction therapy. Whether and how antithrombin may affect leukemia outcome remains to be determined.

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