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J. Greiner et al.
trally by the ALL-BFM study coordination center using comput- er-generated random number lists. This ensured that the partic- ipating centers had no access to the allocation sequence. The assigned arm was submitted to the center by fax.
Patients were randomly assigned to receive one of the two experimental thromboprophylactic treatments with either the low molecular weight heparin enoxaparin or with activity- adjusted antithrombin or to the control arm, i.e., low-dose UFH.
Thromboprophylaxis was started on day 8 and ended on day 33 of induction chemotherapy (Online Supplementary Figure S1). The observation period covered the induction and consolidation phases (Online Supplementary Figure S2) up to and including pro- tocol day 64.
Patients in the enoxaparin group received ClexaneTM at a dose of 80-100 IU/kg body weight once daily subcutaneously31-34 with a target anti-Xa level not exceeding 0.4 U/L, measured 4 h after the third or fourth injection. On days with lumbar puncture or other invasive procedures, enoxaparin was postponed until at least 4 h after the procedure. In the case of thrombocytopenia <30 x 109/L, platelet tranfusion was required or enoxaparin had to be withheld until platelet regeneration.
In the antithrombin group, antithrombin activity was meas- ured every 3 days prior to each asparaginase administration. If antithrombin activity was below the lower limit of normal of 80%, the plasma-derived antithrombin preparation KyberninTM was substituted calculating the dose according to the formula [antithrombintarget 100% – antithrombinactual] x kg body weight targeting at 100% AT activity.
Patients assigned to the control arm received UFH at a dose of 2 IU/kg body weight/h as long as an infusion drip was running to prevent local thrombotic occlusion of the indwelling CVC.24
Treatment with coagulation factors or anticoagulants beyond the interventions intended per protocol was not allowed unless clinically indicated. Management of thromboembolism was at the discretion of the treating physician.
Outcome measures
The diagnosis of thromboembolism was based on clinical sus- picion and had to be confirmed by one or more suitable imaging methods within a routine diagnostic work-up (Online Supplementary Table S1). No systematic provision was made for blinding the attending physicians or radiologists to the random- ization arm. Intermittent dysfunction of the CVC by a clot at the tip of the catheter was not considered a thrombotic event as long as CVC patency was restored. The principal safety out- come was absence of bleeding complications during the study period. The definition of major and minor hemorrhage met internationally defined standards (Online Supplementary Table S2).35-37 Secondary safety outcomes were event-free survival and overall survival. Event-free survival was defined as the time from diagnosis to the date of last follow-up or first event. Events were resistance to therapy, leukemia relapse, secondary neo- plasm or death from any cause. Failure to achieve remission due to early death or resistance was considered as an event at time zero. Survival was defined as time from diagnosis to the date of last follow-up or death from any cause.
Statistical analysis
The primary objective was to test whether antithrombotic prophylaxis with enoxaparin or antithrombin was superior to that with UFH. The null hypothesis was that there was no dif- ference between enoxaparin or antithrombin versus UFH tested with a one-tailed Fisher exact test at a significance level of P=0.025 each. The main analysis was by intention-to-treat. In
order to reach a power of 85% with a significance level of 0.025, 315 patients had to be randomized per group, assuming an event rate of 9% within the UFH group and 3% in the two interven- tional groups. If both comparisons were significantly different, the thrombosis rates in the enoxaparin and antithrombin arm had to be tested for equivalence (secondary objective). Antithrombin replacement and enoxaparin therapy would be considered equivalent if the two-sided 95% confidence interval (95% CI) of the incidence difference did not exceed ±4%. For the equivalence test, patients were analyzed according to the treatment given (as treated).
The Kaplan-Meier method38 was used to estimate survival rates, and differences were compared with the log-rank test.39 A Cox proportional hazards model was used in univariate and multivariate survival analyses.40 Cumulative incidence functions for competing events were constructed by the method of Kalbfleisch and Prentice41 and compared with the Gray test.42 Odds ratios were calculated to compare the risks of thromboem- bolic events. Except for the confirmatory analyses of the pri- mary study question, all other analyses were exploratory.
Results
Patients’ characteristics
From December 1, 2002, to December 31, 2011, 1526 patients with ALL treated at one of the 26 study centers in Germany and Switzerland were eligible for randomiza- tion (Figure 1). Of these, 577 patients were not random- ized, the vast majority because patients and/or parents refused consent to be randomized to the enoxaparin arm as they did not wish to accept a daily subcutaneous injec- tion. Nine hundred and forty-nine patients (the popula- tion for the intention-to-treat analyses) were randomly assigned to receive either UFH (n=312), enoxaparin (n=317) or antithrombin (n=320). Randomized and non- randomized eligible patients did not differ with respect to their initial characteristics (Online Supplementary Table S3). The proportions of patients with a poor response to the prednisone prephase (prednisone poor-responders) and a slow treatment response as assessed by minimal residual disease were significantly higher in the group of non-ran- domized patients. In the intention-to-treat population, numbers and characteristics of patients were well-bal- anced between the three randomization arms except for a slight imbalance in the age distribution with fewer chil- dren below 6 years in the enoxaparin group (Table 1). Patients’ characteristics were evenly distributed between the randomization arms as treated except for a signifi- cantly lower proportion of patients below 6 years of age in the enoxaparin arm (details provided in Online Supplementary Table S4).
The proportion of patients who refused antithrombotic treatment as allocated was 3% in patients randomized to UFH (10/312) or antithrombin (11/320), and 33% (105/317) in those assigned to enoxaparin (Figure 1). Rejection of the enoxaparin arm was more frequent in patients below 6 years of age than in older patients [62/157 (39%) versus 42/160 (27%), respectively] with a preferential switch to UFH in the younger cohort (Online Supplementary Table S5). Based on this finding additional exploratory analyses with respect to thromboembolism rate and leukemia-related outcomes were performed, stratified by age and in the as-treated groups.
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haematologica | 2019; 104(4)