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

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.

Figure 1.

Consolidated standards for reporting of trials (CONSORT) diagram. AT: antithrombin; E: enoxaparin; UFH: unfractionated heparin.

Figure 2.

Thromboembolic events according to the randomization arms. Results are shown by intention to treat (A, C and E) and by treatment as given (B, D and F) for the total cohort (A and B) and stratified by age <6 years (C and D) and ≥6 years (E and F). Events are depicted as cumulative incidence curves. The P values indicated were calculated with the Fisher exact test. CI: confidence interval; OR: odds ratio; TE: thromboembolism; UFH: unfractionated heparin.

Figure 3.

Outcome of acute lymphoblastic leukemia according to the THROMBOTECT randomization arms. (A,B) Event-free survival and (C,D) cumulative incidence of relapse are shown by intention to treat (A,C) and by treatment as given (B,D). Numbers of patients at risk in the event-free survival graphs also apply to the respective relapse incidence graphs. 5 y-pEFS: 5-year probability of event-free survival; 5 y-CIR: 5-year cumulative incidence of relapse; SE: standard error; UFH: unfractionated heparin.