Venous thromboembolism in children with acute lymphoblastic leukemia in China: a report from the Chinese Children’s Cancer Group-ALL-2015

Abstract

Venous thromboembolism (VTE) is a complication in children with acute lymphoblastic leukemia (ALL). The Chinese Children’s Cancer Group-ALL-2015 protocol was carried out in China, and epidemiology, clinical characteristics, and risk factors associated with VTE were analyzed. We collected data on VTE in a multi-institutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019. First, VTE occurred in 159 (2.08%) patients, including 90 (56.6%) during induction therapy and 108 (67.92%) in the upper extremities. T-ALL had a 1.74-fold increased risk of VTE (95% CI 1.08–2.8, P = 0.022). Septicemia, as an adverse event of ALL treatment, can significantly promote the occurrence of VTE (P < 0.001). Catheter-related thrombosis (CRT) accounted for 75.47% (n = 120); and, symptomatic VTE, 58.49% (n = 93), which was more common in patients aged 12–18 years (P = 0.023), non-CRT patients (P < 0.001), or patients with cerebral thrombosis (P < 0.001). Of the patients with VTE treated with anticoagulation therapy (n = 147), 4.08% (n = 6) had bleeding. The VTE recurrence rate was 5.03% (n = 8). Patients with VTE treated by non-ultrasound-guided venous cannulation (P = 0.02), with residual thrombus (P = 0.006), or with short anticoagulation period (P = 0.026) had high recurrence rates. Thus, preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.

Keywords

acute lymphoblastic leukemia / child / venous thromboembolism / epidemiology / clinical characteristic / risk factor

References

[1] Vrooman LM, Silverman LB. Treatment of childhood acute lymphoblastic leukemia: prognostic factors and clinical advances. Curr Hematol Malig Rep 2016; 11(5): 385–394

[2] Levy-Mendelovich S, Barg AA, Kenet G. Thrombosis in pediatric patients with leukemia. Thromb Res 2018; 164(Suppl 1): S94–S97

[3] Cai J, Yu J, Zhu X, Hu S, Zhu Y, Jiang H, Li C, Fang Y, Liang C, Ju X, Tian X, Zhai X, Hao J, Hu Q, Wang N, Jiang H, Sun L, Li CK, Pan K, Yang M, Shen S, Cheng C, Ribeiro RC, Pui CH, Tang J; Chinese Children’s Cancer Group childhood acute lymphoblastic leukaemia (ALL) 2015 study group (CCCG-ALL-2015). Treatment abandonment in childhood acute lymphoblastic leukaemia in China: a retrospective cohort study of the Chinese Children’s Cancer Group. Arch Dis Child 2019; 104(6): 522–529

[4] Betensky M, Kulkarni K, Rizzi M, Jones S, Brandão LR, Faustino EVS, Goldenberg NA, Sharathkumar A. Recommendations for standardized definitions, clinical assessment, and future research in pediatric clinically unsuspected venous thromboembolism: communication from the ISTH SSC subcommittee on pediatric and neonatal thrombosis and hemostasis. J Thromb Haemost 2022; 20(7): 1729–1734

[5] Athale UH, Laverdiere C, Nayiager T, Delva YL, Foster G, Thabane L, Chan AK. Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study. BMC Cancer 2017; 17(1): 313

[6] 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(1): 103–114

[7] Goyal G, Bhatt VR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. Future Oncol 2015; 11(17): 2459–2470

[8] Caruso V, Iacoviello L, Di Castelnuovo A, Storti S, Mariani G, de Gaetano G, Donati MB. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006; 108(7): 2216–2222

[9] Ranta S, Tuckuviene R, Mäkipernaa A, Albertsen BK, Frisk T, Tedgård U, JónssonÓG, Pruunsild K, Gretenkort Andersson N, Winther Gunnes M, Saulyte Trakymiene S, Frandsen T, Heyman M, Ruud E, Helgestad J. Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia—a multicentre study from the Nordic Society of Paediatric Haematology and Oncology. Br J Haematol 2015; 168(4): 547–552

[10] Vu K, Luong NV, Hubbard J, Zalpour A, Faderl S, Thomas DA, Yang D, Kantarjian H, Kroll MH. A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center. Cancer Med 2015; 4(1): 27–35

[11] Rühle F, Stoll M. Advances in predicting venous thromboembolism risk in children. Br J Haematol 2018; 180(5): 654–665

[12] Riondino S, Ferroni P, Zanzotto FM, Roselli M, Guadagni F. Predicting VTE in cancer patients: candidate biomarkers and risk assessment models. Cancers (Basel) 2019; 11(1): E95

[13] Rank CU, Toft N, Tuckuviene R, Grell K, Nielsen OJ, Frandsen TL, Marquart HVH, Albertsen BK, Tedgård U, Hallböök H, Ruud E, Jarvis KB, Quist-Paulsen P, Huttunen P, Wartiovaara-Kautto U, JónssonÓG, Trakymiene SS, Griškevičius L, Saks K, Punab M, Schmiegelow K. Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years. Blood 2018; 131(22): 2475–2484

[14] Klaassen ILM, Lauw MN, Fiocco M, van der Sluis IM, Pieters R, Middeldorp S, van de Wetering MD, de Groot-Kruseman HA, van Ommen CH. Venous thromboembolism in a large cohort of children with acute lymphoblastic leukemia: risk factors and effect on prognosis. Res Pract Thromb Haemost 2019; 3(2): 234–241

[15] Giordano P, Santoro N, Del Vecchio GC, Rizzari C, Masera G, De Mattia D. T-immunophenotype is associated with an increased prevalence of thrombosis in children with acute lymphoblastic leukemia. A retrospective study. Haematologica 2003; 88(9): 1079–1080

[16] Zhu Y, Yang R, Cai J, Yu J, Tang Y, Chen Y, Wang N, He H, Wu X, Cheng FWT, Sun L, He Y, Ju X, Tian X, Hu Q, Jin R, Pan K, Fang Y, Zhai X, Jiang H, Li CK. Septicemia after chemotherapy for childhood acute lymphoblastic leukemia in China: a multicenter study CCCG-ALL-2015. Cancer Med 2020; 9(6): 2113–2121

[17] Esmon CT. Molecular circuits in thrombosis and inflammation. Thromb Haemost 2013; 109(3): 416–420

[18] Cohoon KP, Ashrani AA, Crusan DJ, Petterson TM, Bailey KR, Heit JA. Is infection an independent risk factor for venous thromboembolism? A population-based, case-control study. Am J Med 2018; 131(3): 307–316.e2

[19] Truelove E, Fielding AK, Hunt BJ. The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia. Leukemia 2013; 27(3): 553–559

[20] Reddy P, Dupree L. Practical approach to VTE management in hospitalized patients. Am J Ther 2017; 24(4): e442–e467

[21] Kraaijpoel N, Di Nisio M, Mulder FI, van Es N, Beyer-Westendorf J, Carrier M, Garcia D, Grosso M, Kakkar AK, Mercuri MF, Middeldorp S, Hernandez CR, Santamaria A, Schwocho L, Segers A, Verhamme P, Wang TF, Weitz JI, Zhang G, Zwicker JI, Büller HR, Raskob GE. Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE Cancer Study. Thromb Haemost 2018; 118(8): 1439–1449

[22] Stevens H, Peter K, Tran H, McFadyen J. Predicting the risk of recurrent venous thromboembolism: current challenges and future opportunities. J Clin Med 2020; 9(5): E1582

Acknowledgements

We are grateful for support from VIVA-China Children’s Cancer Foundation and Prof. Pui team. We also appreciate the contributions of all the colleagues and patients.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0958-6 and is accessible for authorized users.

Compliance with ethics guidelines

Mengmeng Yin, Hongsheng Wang, Xianmin Guan, Ju Gao, Minghua Yang, Ningling Wang, Tianfeng Liu, Jingyan Tang, Alex WK Leung, Fen Zhou, Xuedong Wu, Jie Huang, Hong Li, Shaoyan Hu, Xin Tian, Hua Jiang, Jiaoyang Cai, Xiaowen Zhai, Shuhong Shen, and Qun Hu declare no competing interests. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

RIGHTS & PERMISSIONS

2022 Higher Education Press