Page 17 - 2019_04-Haematologica-web

Editorials
Third, THROMBOTECT provides information regard- ing only symptomatic thromboembolic events. However, previous studies in children with ALL and CVC have shown relatively low frequencies of symptomatic throm- boembolic events but substantial frequencies of asympto- matic thromboembolism detected by systematic radi- ographic screening.2 While some believe that sympto- matic thromboembolic events are clinically most relevant, many of the patients with asymptomatic thromboem- bolism in PARKAA had significant degrees of venous occlusion. The THROMBOTECT study did not include radiographic screening (e.g. ultrasound) which would have achieved a more complete identification of both symptomatic and asymptomatic thromboembolism. Moreover, using objective radiographic screening would have reduced the potential for observer bias. To what extent thromboprophylaxis affects asymptomatic throm- boembolism, remains open.
Fourth, while the patients received thromboprophylaxis only during the induction phase they were followed for thromboembolic events and bleeding outcomes into the consolidation phase. One fifth of thromboembolic events and half of the bleeds occurred during induction consoli- dation. Therefore, as the study interventions had already been discontinued, their association with these outcome events cannot be definitively determined.
The manuscript presents an exploratory subgroup analysis based on age. In children >6 years, frequencies of thromboembolic events were higher (6.4%) and differ- ences between treatment arms more pronounced, while in younger children, thromboembolic events were observed less frequently (2.7%) and not significantly different between arms. This possible age effect should be inter- preted with caution, because thromboembolic events may not be detected in younger children as symptoms may be reported to a lesser extent. Treatment effects were quali- tatively not different for younger children, and a benefit from anticoagulant prophylaxis, even if smaller, may be extrapolated from older children. Given that there were few bleeding events, using thromboprophylaxis in chil- dren of all ages appears reasonable.
One notable observation made in the THROMBOTECT study was the large proportion of children/families that refused LMWH due to subcutaneous injections. Of eligi- ble patients at participating centers, 38% would not con- sent to enter the study. Among consenting participants, of those randomised to LMWH, 33% refused this treatment due to subcutaneous injections. While the difficulty in treating children with subcutaneous drugs is well known by pediatricians, the THROMBOTECT study provides solid evidence documenting the magnitude of the problem and concludes that there are problems with compliance with anticoagulant drugs administered subcutaneously.
Although antithrombin was effective at decreasing the incidence of thromboembolic events with no additional risk of bleeding, the unexpected finding that patients receiving antithrombin had an increased rate of relapse is an issue. As this association was not constant over a num-
ber of analyses, it may well be a chance finding. However, a biological effect of antithrombin substitution on leukemia outcome cannot be completely excluded and so the use of antithrombin for thromboprophylaxis cannot be recommended until more evidence is available. Moreover, antithrombin concentrate is expensive, and substitution requires monitoring of antithrombin levels and intravenous infusion which is a burden to the patient. Therefore, while THROMBOTECT has shown that both antithrombin and LMWH are effective at preventing thromboembolic events, there remain challenges with these choices for thromboprophylaxis.
The authors of the paper conclude that the THROMBO- TECT results provide the rationale to develop new studies to further determine best practice in preventing throm- boembolic events in pediatric ALL. An ongoing clinical trial, the PREVAPIX-ALL (NCT02369653) study is a ran- domized controlled trial determining the efficacy and safety of primary prophylaxis with apixaban in preven- tion of thromboembolic events in pediatric patients with ALL/lymphoblastic lymphoma during induction chemotherapy. A total of 500 participants are randomized to apixaban (intervention) or no systemic anticoagulation (control). Subjects are followed for symptomatic throm- boembolic events and all patients are screened for throm- boembolism by ultrasound and echocardiography at the end of the induction phase. Apixaban is a direct oral anti- coagulant and has been shown in adults to require no monitoring, making it an attractive option in children. The importance of availability of an oral anticoagulant is underscored by the results of THROMBOTECT with respect to the limited acceptance of subcutaneously inject- ed LMWH. While the PREVAPIX-ALL study is open label, bias is minimized by the screening of all participants at the end of the study using standardized imaging tests and a blinded central adjudication committee.
In conclusion, THROMBOTECT has established a pos- itive benefit-risk balance for primary thromboprophylaxis in children with ALL. PREVAPIX-ALL will add to these findings by assessing the efficacy and safety of a direct oral anticoagulant in this population. These studies will determine the optimum clinical approach for the preven- tion of thromboembolic events in pediatric ALL, and pro- vide the basis for further studies of thromboprophylaxis in children in other settings.
References
1. Vidal E, Sharathkumar A, Glover J, Faustino EV. Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis. J Thromb Haemost. 2014;12(7):1096-1109.
2. Mitchell L, Andrew M, Hanna K, et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in chil- dren receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost. 2003;90(2):235-244.
3. Greiner J, Schrappe M, Claviez A, et al. THROMBOTECT - a ran- domized study comparing low molecular weight heparin, antithrom- bin and unfractionated heparin for thromboprophylaxis during inud- ction therapy of acute lymphoblastic leukemia in children and adoles- cents. Haematologica. 2019;104(4):756-765.
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