Page 136 - 2019_04-Haematologica-web

J. Greiner et al.
at predefined time points. This comprises ultrasound but also magnetic resonance imaging which, in young chil- dren, often requires general anesthesia. In addition, for the time being the appropriate time points to look for vessel occlusion are not known and hence the possibility of missing a thrombosis at arbitrarily chosen time points would be high. Exposing children to repeated extra anes- thesia with a questionable benefit was considered too high an additional burden. The study design chosen was, therefore, in favor of an open-label treatment. Imaging was performed on clinical suspicion despite the acknowl- edged inherent drawbacks.
Evaluation of event-free survival and relapse rate within the THROMBOTECT randomization groups revealed the unexpected finding that patients randomized to the antithrombin group had a higher incidence of relapse com- pared to those in the enoxaparin and UFH groups. The dif- ferences were no longer obvious in the as-treated analysis and were apparent in the medium-risk group only. Although a causal relationship between the cumulative antithrombin dose and the relapse rate could not be estab- lished, the possibility that antithrombin substitution might affect leukemia outcome cannot be entirely excluded.
In conclusion, the THROMBOTECT study has, for the
first time, demonstrated that activity-targeted antithrom- bin replacement as well as the use of enoxaparin lead to a significant risk reduction for thromboembolism during ALL induction therapy when compared with low-dose UFH. Bleeding was not a major concern. Thromboprophylaxis during induction therapy can, therefore, be recommended for children and adolescents with ALL. The higher incidence of late relapses in chil- dren with medium-risk ALL assigned to the antithrombin group remains to be resolved and leads us to recommend, at present, primarily enoxaparin. Whether thrombopro- phylaxis contributes to minimize not only clinical but also silent thromboses and by that long-term morbidity in terms of post-thrombotic syndrome remains to be deter- mined. The THROMBOTECT results provide the ration- ale for new studies, both to elucidate a possible impact of antithrombin on leukemia outcome and to further deter- mine the best practice to prevent thromboembolism dur- ing ALL induction chemotherapy.
Acknowledgments
We thank the investigators, the medical staff, the data man- agers and the patients of all participating centers for their sus- tained support of the THROMBOTECT study.
References
1 Athale UH, Chan AK. Thrombosis in chil- dren with acute lymphoblastic leukemia. Part I. Epidemiology of thrombosis in chil- dren with acute lymphoblastic leukemia. Thromb Res. 2003;111(3):125-131.
2 Mitchell L, Hoogendoorn H, Giles AR, Vegh P, Andrew M. Increased endogenous throm- bin generation in children with acute lym- phoblastic leukemia: risk of thrombotic complications in L-asparaginase-induced antithrombin III deficiency. Blood. 1994;83(2):386-391.
3 Mitchell LG, Sutor AH, Andrew M. Hemostasis in childhood acute lymphoblas- tic leukemia: coagulopathy induced by dis- ease and treatment. Semin Thromb Hemost. 1995;21(4):390-401.
4 Nowak-Göttl U, Ahlke E, Fleischhack G, et al. Thromboembolic events in children with acute lymphoblastic leukemia (BFM proto- cols): prednisone versus dexamethasone administration. Blood. 2003;101(7):2529- 2533.
5 Caruso V, Iacoviello L, di Castelnuovo A, et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta- analysis of 17 prospective studies compris- ing 1752 pediatric patients. Blood. 2006;108(7):2216-2222.
6 Mitchell LG, Andrew M, Hanna K, et al. A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L- asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) study. Cancer. 2003;97(2):508-516.
7 Journeycake JM, Buchanan GR. Catheter- related deep venous thrombosis and other catheter complications in children with can-
cer. J Clin Oncol. 2006;24(28):4575-4580.
8 Male C, Chait P, Andrew M, Hanna K, Julian J, Mitchell L. Central venous line-related thrombosis in children: association with central venous line location and insertion
technique. Blood. 2003;101(11):4273-4278. 9 Athale UH, Chan AK. Thrombosis in chil- dren with acute lymphoblastic leukemia. Part II. Pathogenesis of thrombosis in chil- dren with acute lymphoblastic leukemia: effects of the disease and therapy. Thromb
Res. 2003;111(4-5):199-212.
10 Astwood E, Vora A. Personal practice: how
we manage the risk of bleeding and throm- bosis in children and young adults with acute lymphoblastic leukaemia. Br J Haematol. 2011;152(5):505-511.
11 Vidal E, Sharathkumar A, Glover J, Faustino EV. Central venous catheter-related throm- bosis and thromboprophylaxis in children: a systematic review and meta-analysis: reply. J Thromb Haemost. 2015;13(1):161-162.
12 Wiernikowski JT, Athale UH. Thromboembolic complications in children with cancer. Thromb Res. 2006;118(1):137- 152.
13 Athale UH, Siciliano SA, Crowther M, Barr RD, Chan AK. Thromboembolism in chil- dren with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute pro- tocols: effect of age and risk stratification of disease. Br J Haematol. 2005;129(6):803-810.
14 Tuckuviene R, Ranta S, Albertsen BK, et al. Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study. J Thromb Haemost. 2016;14(3):485-494.
15 Nowak-Göttl U, Wermes C, Junker R, et al. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 geno- type, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood. 1999;93(5):1595-1599.
16 Mitchell L, Andrew M, Hanna K, et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost. 2003;90(2):235-244.
17 Avila ML, Duan L, Cipolla A, et al. Postthrombotic syndrome following upper extremity deep vein thrombosis in children. Blood. 2014;124(7):1166-1173.
18 Gugliotta L, D'Angelo A, Mattioli BM, et al. Hypercoagulability during L-asparaginase treatment: the effect of antithrombin III sup- plementation in vivo. Br J Haematol. 1990;74(4):465-470.
19 Nowak-Göttl U, Kuhn N, Wolff JE, et al. Inhibition of hypercoagulation by antithrombin substitution in E. coli L- asparaginase-treated children. Eur J Haematol. 1996;56(1-2):35-38.
20 Elhasid R, Lanir N, Sharon R, et al. Prophylactic therapy with enoxaparin dur- ing L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis. 2001;12(5):367-370.
21 Harlev D, Zaidman I, Sarig G, Ben Arush MW, Brenner B, Elhasid R. Prophylactic ther- apy with enoxaparin in children with acute lymphoblastic leukemia and inherited thrombophilia during L-asparaginase treat- ment. Thromb Res. 2010;126(2):93-97.
22 Ruud E, Holmstrom H, de Lange C, Natvig S, Albertsen BK, Wesenberg F. Thrombotic effects of asparaginase in two acute lym- phoblastic leukemia protocols (NOPHO ALL-1992 versus NOPHO ALL-2000): a sin- gle-institution study. Pediatr Hematol Oncol. 2006;23(3):207-216.
23 Meister B, Kropshofer G, Klein-Franke A, Strasak AM, Hager J, Streif W. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute
764
haematologica | 2019; 104(4)