PREVAPIX-ALL: Apixaban Compared to Standard of Care for Prevention of Venous Thrombosis in Paediatric Acute Lymphoblastic Leukaemia (ALL)—Rationale and Design

Abstract

Venous thromboembolic (VTE) complications in children and adolescents with acute lymphoblastic leukaemia (ALL) and T or B cell lymphoblastic lymphoma (T/B cell LL) can result not only in life-threatening acute complications but also contribute to significant long-term sequelae. The PREVAPIX-ALL study is an open-label randomized controlled study comparing outcomes of treatment with prophylactic dose apixaban versus no anticoagulation (standard of care) in children and adolescents with ALL and T/B cell LL receiving standard induction chemotherapy with asparaginase and the presence of a central venous access device. On day 29 of induction, all patients undergo screening imaging with duplex ultrasonography and echocardiography. The primary efficacy endpoint of the study is a composite of symptomatic and asymptomatic VTE that includes deep vein thrombosis, pulmonary embolism, cerebral sinovenous thrombosis or VTE-related death. The primary safety outcome is major bleeding. Secondary outcomes are central line-associated infections, patency and line replacement, superficial thrombosis, arterial events and death. A planned sample size of 500 randomized paediatric patients enrolled over a period of 5 years is based on the estimation of VTE rates of 20 and 10% in the standard of care and apixaban groups, respectively. An optional biomarker study in 150 patients will examine predictors of increased VTE risk and study in vivo anticoagulant effects of apixaban in children by measuring specific biomarkers in the haemostatic system and inflammatory pathway. This study will provide valuable information for the safety and efficacy of apixaban in VTE prevention during induction in paediatric ALL.

Keywords

anticoagulation - deep vein thrombosis - direct-acting oral anticoagulant - thromboprophylaxis - children

• References

• 1 Levy-Mendelovich S, Barg AA, Kenet G. Thrombosis in pediatric patients with leukemia. Thromb Res 2018; 164 (Suppl. 01) S94-S97
• 2 Caruso V, Iacoviello L, Di Castelnuovo A. , et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006; 108 (07) 2216-2222
• 3 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 (03) 485-494
• 4 Mitchell LG, Andrew M, Hanna K. , et al; Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase Group (PARKAA). 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 (02) 508-516
• 5 Bezeaud A, Drouet L, Leverger G, Griffin JH, Guillin MC. Effect of L-asparaginase therapy for acute lymphoblastic leukemia on plasma vitamin K-dependent coagulation factors and inhibitors. J Pediatr 1986; 108 (5 Pt 1): 698-701
• 6 Mall V, Thomas KB, Sauter S, Niemeyer CM, Sutor AH. Effect of glucocorticoids, E. coli- and Erwinia L-asparaginase on hemostatic proteins in children with acute lymphoblastic leukemia. Klin Padiatr 1999; 211 (04) 205-210
• 7 Nowak-Göttl U, Kenet G, Mitchell LG. Thrombosis in childhood acute lymphoblastic leukaemia: epidemiology, aetiology, diagnosis, prevention and treatment. Best Pract Res Clin Haematol 2009; 22 (01) 103-114
• 8 Massicotte P, Mitchell L. Thromboprophylaxis of central venous lines in children with cancer: the first steps taken on the long road ahead. Acta Paediatr 2006; 95 (09) 1049-1052
• 9 Kuhle S, Spavor M, Massicotte P. , et al. Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost 2008; 6 (04) 589-594
• 10 Kulkarni K, Halton J, Spavor M. , et al. Increased requirement for central venous catheter replacement in paediatric oncology patients with deep venous thrombosis: a multicentre study. Thromb Haemost 2015; 113 (02) 434-435
• 11 Silverman LB, Gelber RD, Dalton VK. , et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97 (05) 1211-1218
• 12 Athale U, Cox S, Siciliano S, Chan AK. Thromboembolism in children with sarcoma. Pediatr Blood Cancer 2007; 49 (02) 171-176
• 13 Zia AN, Chitlur M. Management of thrombotic complications in acute lymphoblastic leukemia. Indian J Pediatr 2013; 80 (10) 853-862
• 14 Levine MN, Gu C, Liebman HA. , et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost 2012; 10 (05) 807-814
• 15 Kimpton M, Wells PS, Carrier M. Apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients receiving chemotherapy: rational and design of the AVERT trial. Thromb Res 2018; 164 (Suppl. 01) S124-S129
• 16 Ruud E, Holmstrøm H, Natvig S, Wesenberg F. Prevalence of thrombophilia and central venous catheter-associated neck vein thrombosis in 41 children with cancer--a prospective study. Med Pediatr Oncol 2002; 38 (06) 405-410
• 17 Massicotte P, Julian JA, Gent M. , et al; PROTEKT Study Group. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003; 109 (2-3): 101-108
• 18 Elhasid R, Lanir N, Sharon R. , et al. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis 2001; 12 (05) 367-370
• 19 Massicotte P, Julian JA, Gent M. , et al; REVIVE Study Group. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109 (2-3): 85-92
• 20 Greiner J, Schrappe M, Claviez A. , et al. THROMBOTECT - a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents. Haematologica 2018 . Doi: haematol.2018.194175
• 21 Bristol-Myers Squibb. A Study of the Safety and Effectiveness of Apixaban in Preventing Blood Clots in Children With Leukemia Who Have a Central Venous Catheter and Are Treated With Asparaginase; 2015 . Available at: https://clinicaltrials.gov/ct2/show/NCT02369653 . Accessed May 29, 2018
• 22 Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’. In: European Medicines Agency; 2017
• 23 Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5 (12) 2368-2375
• 24 Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. ; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375 (9717): 807-815
• 25 Centers for Disease Control and Prevention. National Healthcare Safety Network. Surveillance for Central Line-Associated Bloodstream Infections (CLABSI). Central line-associated bloodstream infections (CLABSI) event. Available at: www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf . Accessed February 13, 2019
• 26 Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Göttl U. ; Perinatal and Paediatric Haemostasis Subcommittee of the SSC of the ISTH. Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9 (09) 1856-1858
• 27 Mitchell L, Ruehle F, Brandao L, Halton J, Israels S, Dietrich K, Spavor M, Stoll M. , ABLE Investigators. Development of a predictive risk model for deep vein thrombosis in pediatric oncology patients. Res Pract Thromb Haemost 2017; ;(1, S1): 1-15
• 28 Klaassen ILM, Lauw MN, van de Wetering MD. , et al. TropicALL study: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin: a multicenter randomized controlled trial. BMC Pediatr 2017; 17 (01) 122
• 29 Journeycake JM, Buchanan GR. Catheter-related deep venous thrombosis and other catheter complications in children with cancer. J Clin Oncol 2006; 24 (28) 4575-4580
• 30 Madenci AL, Weil BR, Liu Q. , et al. Long-term risk of venous thromboembolism in survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2018; JCO2018784595
• 31 Male C, Chait P, Ginsberg JS. , et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase. Thromb Haemost 2002; 87 (04) 593-598
• 32 Monagle P, Cochrane A, Roberts R. , et al; Fontan Anticoagulation Study Group. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children. J Am Coll Cardiol 2011; 58 (06) 645-651
• 33 Winick N, Devidas M, Chen S. , et al. Impact of initial CSF findings on outcome among patients with National Cancer Institute Standard- and high-risk B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. J Clin Oncol 2017; 35 (22) 2527-2534
• 34 Rank CU, Toft N, Tuckuviene R. , et al. Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years. Blood 2018; 131 (22) 2475-2484