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Thromboembolism and thromboprophylaxis in pediatric ALL
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 lym- phoblastic leukemia during induction therapy. Whether and how antithrombin may affect leukemia out- come remains to be determined.
Introduction
Thromboembolism is a serious complication of gluco- corticoid and E. coli asparaginase-containing induction therapy for childhood acute lymphoblastic leukemia (ALL). Reported incidences vary between 1% and 37%, depending on the study design and definition of throm- bosis, as well as diagnostic, supportive and therapeutic methods.1-6 Acquired antithrombin deficiency as a result of asparaginase-induced asparagine depletion is consid- ered to be a crucial mechanism for the development of thromboembolism during ALL induction therapy. The presence of a central venous catheter (CVC) seems to be an additional – at least local – risk factor for thromboem- bolism as a significant proportion of thromboembolic events during ALL treatment is related to an indwelling CVC. Furthermore, the risk of thromboembolism has been shown to be associated with CVC location and insertion technique.1,5,7-12 Published data also provide good evidence that adolescent age is an important risk factor for thromboembolism whereas the additional impact of inherited thrombophilia in the context of childhood ALL treatment is controversial.5,13-16
Sufficiently powered randomized trials on thrombo- prophylaxis in children during ALL induction therapy have not been available,16-23 and evidence for the benefit of specific thromboprophylactic measures has therefore been lacking so far. In the absence of valid medical stan- dards of care regarding thromboprophylaxis and the use of a CVC during ALL induction, various different approaches existed in the pediatric cancer centers in Switzerland and Germany in the early 2000s, each based on individual experiences and institutional standards. This unsatisfactory situation gave the impetus to initiate the THROMBOTECT trial, a prospective randomized study to evaluate the efficacy and safety of antithrombot- ic prophylaxis in children treated for ALL.
As drug administration through an indwelling CVC provides significant gain in comfort for the patients and increases the safety of therapy with tissue-toxic agents, the THROMBOTECT study was initially designed to include patients with implanted CVC from the initiation of the induction phase and was only later on also opened for patients without CVC. Two mechanisms of action to prevent thromboembolism were utilized in the two inter- ventional arms of the trial: inhibition of thrombin through inactivation of coagulation factor X by treatment with the low molecular weight heparin enoxaparin (ClexaneTM) and replacement of antithrombin by the plas- ma-derived antithrombin preparation KyberninTM to com- pensate for asparaginase-related aquired antithrombin deficiency. Being aware of the published data of Nowak- Göttl et al., which reported an almost 50% incidence of
thromboembolism among ALL patients with a prothrom- botic defect, and considering the additional risk factor of an indwelling CVC, a control arm without any interven- tion appeared difficult to justify.15 The third arm therefore included continuous infusion of low-dose unfractionated heparin (UFH) while the CVC was in use, with the aim of preventing local clot formation at the tip of the catheter, thereby preventing thrombotic occlusion of the indwelling CVC without causing relevant systemic anti- coagulatory effects.7,24-27 Low-dose UFH was, therefore, considered the control arm.
The current report presents the clinical results of the THROMBOTECT study with respect to the incidence of symptomatic thromboembolism and hemorrhage as pri- mary efficacy and safety outcomes as well as the second- ary safety outcome of leukemia-related survival.
Methods
Study design
THROMBOTECT was an open-label, prospective, random- ized, multicenter study to evaluate two different preventive antithrombotic measures during induction chemotherapy in children with ALL treated according to ALL-BFM 2000 (NCT 00430118) and AIEOP-BFM-ALL 2009 treatment protocols (NCT 01117441). THROMBOTECT was an add-on study to the ALL- BFM protocols and was approved by the leading ethics commit- tees of the Medical School Hannover, Germany, and St. Gallen, Switzerland, and by the local ethics committees of each partici- pating site. Written informed consent to participation in the study was obtained from guardians and/or patients before ran- domization. The detailed study protocol is available in the Online Supplementary Material.
Patients’ eligibility
Patients were eligible if treated on the ALL-BFM 2000 or AIEOP-BFM ALL 2009 protocol,28-30 if they had a CVC inserted by day 8 of induction and if the CVC remained in place until at least day 33. The choice of the CVC and decisions regarding its maintenance were made by the treating physicians according to institutional guidelines. In August 2004, the protocol was amended to allow participation of patients without a CVC. Exclusion criteria were known hemorrhagic disorders unrelated to leukemia, active gastrointestinal ulcer, previous cerebrovascu- lar accident and/or known hypersensitivity to heparin.
Randomization and study treatment
After written informed consent had been given, randomiza- tion was performed by day 8 in a 1:1:1 ratio using permuted blocks of six patients and stratification by country and the glu- cocorticoid preparation (dexamethasone or prednisone) admin- istered during induction.29 Randomization was performed cen-
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