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Editorials
THROMBOTECT takes the lead
Christoph Male,1 Sarah H. O’Brien2 and Lesley Mitchell3
1Department of Pediatrics, Medical University of Vienna, Austria; 2Division of Hematology & Oncology, Nationwide Children’s Hospital, Columbus, OH, USA and 3Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alberta, AB, Canada
E-mail: CHRISTOPH MALE - christoph.male@meduniwien.ac.at doi:10.3324/haematol.2018.209528
Thromboembolic events in children predominantly occur as secondary complications of severe under- lying diseases and their treatment, the most impor- tant risk factor being the use of central venous catheters (CVC). In spite of the relative high frequency of throm- boembolic events in children with CVC, the evidence to date is equivocal as to whether there is benefit of primary thromboprophylaxis in reducing the risk of these events and whether it outweighs the risk of bleeding in sick chil- dren.1
One population at particular risk of thromboembolic events consists of children receiving induction chemother- apy for pediatric acute lymphoblastic leukemia (ALL). The mechanism implicated in the development of throm- boembolic events is hypothesized to be associated with an acquired antithrombin deficiency resulting from treat- ment with asparaginase. The only randomized trial to date (PARKAA) assessed primary thromboprophylaxis using antithrombin replacement in children with ALL and CVC during induction chemotherapy. However, PARKAA was a feasibility study with limited power and only showed a trend to efficacy of antithrombin replacement.2
In the current issue of Haematologica, Greiner et al. report on the THROMBOTECT study which was an open-label, randomized controlled trial assessing the effi- cacy and safety of primary thromboprophylaxis during induction chemotherapy including asparaginase for ALL in children and adolescents, the majority of whom had a CVC.3 The study, an investigator-initiated study per- formed within the Berlin-Frankfurt-Munster cooperative group, recruited 949 patients who were randomized to three arms: activity-adapted antithrombin substitution, prophylactic-dose low molecular weight heparin (LMWH), or low-dose unfractionated heparin (UFH) as their standard of care. The low UFH dose was intended to prevent CVC occlusion but presumably did not achieve a systemic antithrombotic effect, so this arm might be con- sidered a placebo arm. The primary efficacy outcome was symptomatic thromboembolic events, the principal safety outcome was bleeding, assessed during both induction and consolidation chemotherapy. Secondary safety out- comes were event-free survival and overall survival from the underlying ALL.
The results of the study show a significant reduction in the incidence of thromboembolic events with use of antithrombin (1.9%) and LMWH (3.5%) compared to UFH (8.0%). Since a large proportion of children assigned to LMWH crossed over to other arms, an as-treated analy- sis was performed, showing approximately equal reduc- tions in thromboembolic events risk for antithrombin and LMWH compared to UFH. The incidence of bleeding was low (0.9%) and not different between the three arms.
Regarding leukemia outcome, there was an increased relapse rate in children randomized to antithrombin when compared to those randomized to UFH in the intention- to-treat analysis, but no difference in the as-treated analy- sis. The authors conclude that thromboprophylaxis should be recommended during ALL induction therapy and, given the unclear effect of antithrombin substitution on leukemia outcome, they recommend LMWH as the primary choice at present.
The THROMBOTECT study is an important break- through, as it is the first adequately powered randomized trial of primary thromboprophylaxis in pediatric patients. The study shows that thromboprophylaxis with antithrombin or LMWH is effective at preventing throm- boembolic events without increasing the risk of bleeding. The THROMBOTECT collaborators can be commended for their outstanding effort in completion of this impor- tant study, which will improve the care of children with ALL. Moreover, the study serves as proof-of-concept for thromboprophylaxis in children in other clinical settings. The completion of the study will not only have a signifi- cant impact on clinical management, but will also demon- strate that pediatric clinical trials of anticoagulation can be completed.
As with all clinical trials, particularly in children, there are limitations to the study. First, the study was not masked for practical and ethical reasons, as this would have required placebo subcutaneous injections which would have been unacceptable to children and caregivers. The lack of masking increased the potential for cross-over between treatment arms, diminishing the distinction between arms. Of the patients assigned to LMWH, 33% refused the intervention after randomization because of the subcutaneous injections, of whom approximately two-thirds received UFH or no thromboprophylaxis and one-third were given antithrombin substitution. The study design is problematic in that patients who crossed over were allowed to choose between treatment arms, creating an additional source of selection bias. However, the intention-to-treat and the as-treated analyses are rea- sonably concordant, so the reduction in risk of throm- boembolic events with antithrombin and LMWH throm- boprophylaxis is still valid.
Second, the open-label study treatment, in combination with the primary outcome being clinically symptomatic thromboembolic events, implies a risk of diagnostic suspi- cion bias in outcome assessment. Although clinically sus- pected thromboembolic events were required to be con- firmed by objective radiographic imaging, neither attend- ing physicians nor radiologists were masked to treatment allocation. Moreover, there was no central independent adjudication of outcome events.
haematologica | 2019; 104(4)