Page 134 - 2019_04-Haematologica-web

J. Greiner et al.
A
B
C
D
Figure 3. Outcome of acute lymphoblastic leukemia according to the THROMBOTECT randomization arms. (A,B) Event-free survival and (C,D) cumulative incidence of relapse are shown by intention to treat (A,C) and by treatment as given (B,D). Numbers of patients at risk in the event-free survival graphs also apply to the respec- tive relapse incidence graphs. 5 y-pEFS: 5-year probability of event-free survival; 5 y-CIR: 5-year cumulative incidence of relapse; SE: standard error; UFH: unfrac- tionated heparin.
ized patients (THROMBOTECT cohort: 5-year probabil- ity of event-free survival 84.3±1.2%, 5-year cumulative incidence of relapse 11.7±1.1%; non-randomized patients: 5-year probability of event-free survival 84.0±1.6%, 5-year cumulative incidence of relapse 11.8±1.4). Patients randomized to the antithrombin arm had a 5-year probability of event-free survival of 80.9±2.2% compared with those assigned to enoxaparin (86.2±2.0%, P=0.10) or UFH (85.9±2.0%, P=0.06) (Figure 3A) with a hazard ratio of 1.40 (1.02-1.92; P=0.040) for the antithrombin arm versus the remaining patients. The probability of overall survival at 5 years was similar in all three arms (antithrombin 89.8±1.7%, enoxaparin 90.9±1.6%, UFH 92.4±1.5%). The differences observed in the event-free survival were due to a higher incidence of late relapses in the antithrombin group that in the other groups (Figure 3C); the as-treated analyses showed no statistically significant differences between the three groups [hazard ratio for the antithombin group versus the other groups: 1.16 (0.84-1.59); P=0.37) (Figure 3B,D). Retrospective exploratory subgroup analyses revealed a higher incidence of relapse among the antithrombin- treated patients, but only within the medium-risk group (Online Supplementary Figure S3). Multivariate Cox regres- sion analyses on event-free survival were performed including risk group according to respective trial criteria, TEL-AML1 status, initial white blood cell count, age and the THROMBOTECT arm as covariates. Hazard ratios
for the antithrombin arm were 1.38 (0.99-1.91; P=0.054) for the intention-to-treat analysis and 1.19 (0.86-1.66; P=0.269) for the as-treated analysis and thus comparable with those of the univariate analyses (Online Supplementary Table S6).
To test for a potential dose effect of antithrombin, doses given were analyzed in patients treated in the antithrombin arm. Data available for 248 of 341 patients (72.7%) did not disclose a dose-related effect on the relapse incidence (Online Supplementary Figure S4).
Discussion
Reliable data on thromboembolism during induction
therapy of childhood ALL are scarce. The only random-
ized interventional trial was the PARKAA trial
(Prophylactic antithrombin replacement in kids with ALL
treated with L-asparaginase), designed to determine
whether there was a trend to efficacy and safety of
antithrombin treatment but not powered to prove it.16 To
our knowledge, no other data from adequately designed
and powered studies have been available so far to provide
sufficient evidence that would allow valid recommenda- tions.4,5,9,19,20,23,43,44
The THROMBOTECT trial shows, for the first time, that prophylactic antithrombotic interventions signifi- cantly reduce thromboembolism during ALL induction
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haematologica | 2019; 104(4)