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Thromboembolism and thromboprophylaxis in pediatric ALL
therapy as compared to a control. Both interventions, enoxaparin and activity-adapted Antithrombin substitu- tion, were equally effective. Asparaginase-induced antithrombin deficiency is assumed to be the most impor- tant mechanism for the development of thromboem- bolism during ALL induction therapy.45 As a consequence of asparagine depletion, asparaginase therapy leads to intracellular retention of a misfolded antithrombin, result- ing in acquired antithrombin deficiency.45,46 The THROM- BOTECT trial demonstrated that maintaining antithrom- bin activity at 80% or higher throughout the induction phase could significantly protect patients from throm- boembolism. Thus, correction of low antithrombin activ- ity seems to be one effective way to prevent thromboem- bolism, this being consistent with clinical and laboratory data on antithrombin supplementation.10,16,18,19,47
A considerable number of patients eligible for the study were not randomized. In this group the rate of pred- nisone poor-responders was significantly higher than in the THROMBOTECT cohort. This may be attributed to a tendency of the doctors or parents to avoid additional burden from interventions of an add-on trial in particular in those patients with very poor response during the first days of treatment. However, patients’ characteristics were comparable between the three randomization groups except for a slight underrepresentation of younger patients assigned to enoxaparin. The main reason for not participating was refusal to accept the daily subcutaneous enoxaparin injections. Not surprisingly, the proportion of patients and parents refusing the assigned enoxaparin was highest in young children. This demonstrates not only their reluctance to receive injections but also under- lines a considerable drawback in practical use, irrespec- tive of the antithrombotic efficacy of enoxaparin.
Older age proved to be an important risk factor for thromboembolism, as has been reported earlier by oth- ers.1,13,48 The best cut-off in our data was the age of 6 years. Exploratory analyses suggested that the benefit from either experimental arm was more pronounced in older patients than in young children. The significant benefit in risk reduction of thromboembolism with either intervention, enoxaparin or antithrombin, as com- pared to UFH, provides a convincing rationale for throm- boprophylaxis in this age group. For younger children, the incidence of thromboembolism was low and compa- rable in all three randomization arms. The need for thromboprophylaxis in ALL patients below 6 years of age could, therefore, be questioned. However, the study was not powered for subgroup analyses and the lack of statistical difference in the incidences of thromboem- bolism between the treatment groups in younger chil- dren may be due to insufficient power caused by the number of patients as well as the lower incidence of thromboembolism. Furthermore, in younger children thromboembolism may be missed as symptoms are often subtle. This is in line with the findings of the PARKAA study, which showed that children with symp- tomatic thromboembolism tend to be older than those with clinically asymptomatic thromboembolism.16 Even if clinically not diagnosed, asymptomatic thromboem- bolism may be associated with significant vessel occlu- sion.16 This, in turn, can lead to destruction of the vessel wall, causing long-term morbidity in terms of post- thrombotic syndrome, likely becoming apparent years after the end of ALL therapy. Whether this applies to
young patients with ALL remains unknown.17 Future studies with sufficient statistical power are needed to ascertain whether such interventions in small children are justified. Nevertheless, although the high proportion of patients who refused allocation to the enoxaparin arm may complicate the interpretation of the results in this treatment arm, the reduction of thromboembolism in the global analysis appears to be sufficiently convincing to recommend thromboprophylaxis not only for older patients but for all age groups, all the more as hemor- rhage is of no concern.
Most thrombotic events occurred between induction treatment day 9 and 36, the latter marking the start of induction consolidation. This confirms our experience that thromboembolism only rarely occurs at the time of ALL diagnosis but rather in the course of induction ther- apy. Furthermore, not all centers were able to get a CVC inserted at the time of ALL diagnosis. For these reasons, thromboprophylaxis was started after the prednisone prephase on day 8 of induction therapy. The primary objective of the THROMBOTECT trial was to evaluate efficacy and safety of different prophylactic antithrom- botic interventions during ALL induction therapy. The duration of thromboprophylaxis was, therefore, limited to induction therapy until day 33. Some of the throm- boembolic events occurred after the end of the induction phase. However, only a few of these patients had already started the consolidation phase when the thrombosis was diagnosed. Factors that may have contributed to these late thromboses could be concurrent medical issues such as infections. Given the gradual development of a clot, a still asymptomatic thrombosis might have started to develop towards the end of induction therapy and only become symptomatic in early induction consolidation. Since pegylated asparaginase is presently used more fre- quently - in the AIEOP-BFM ALL 2009 trial, the second dose of this drug was given on day 26 of induction - late thromboses in induction consolidation might become more relevant as the use of pegylated asparaginase may lead to longer asparagine depletion with disturbed coagu- lation patterns, including extended dysfunction of antithrombin. Irrespective of possible concomitant pro- thrombotic risk situations, the hypercoagulable state seems to remain beyond the end of induction therapy. Given the very low rate of hemorrhage it might, there- fore, be advisable to extend thromboprophylaxis accord- ingly.
The open label assignment as well as the diagnosis of thromboembolism made on clinical suspicion only are drawbacks of the THROMBOTECT study design. However, masking the antithrombotic intervention would have meant that all patients in all randomization groups would have had to have been given subcutaneous injections, including those in the UFH and antithrombin groups containing placebo. To conduct the study as a double-blinded trial with double dummy subcutaneous injections was not considered feasible in a large pediatric population.
Similar concerns apply to the primary outcome defined as thromboembolism based on clinical suspicion. The PARKAA study showed that a high incidence of clinically not recognized thromboses can be found by routine imag- ing screening.16 To overcome observer bias, various and repeated routine imaging screening for vessel occlusion at all possible anatomical sites would have been mandatory
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