Magnetic Resonance Screening for Cerebral Venous Sinus Thrombosis during Treatment with Pegaspargase

Abstract

In children with leukemia, cerebral venous sinus thrombosis (CVST) has a significant incidence and mortality rate, which may interfere with the chemotherapy process and lead to long-term neurological complications. However, large studies and population-based data on CVST in children are scarce. This study aims to characterize pediatric CVST associated with pegaspargase (PEG-ASP) and evaluate the significance of magnetic resonance venography (MRV) screening following induction remission in acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). We present a retrospective cohort of a total of 27 children with CSVT and ALL/LBL. The study covers a 4-year period for MRV screening following induction remission and an 8-year comparison period, involving 716 children treated at the Department of Hematology, Children's Hospital of Fudan University. The detection rate of CVST significantly increased after MRV screening (8.4% vs. 1.6%, p < 0.01). Over half (58%) of the CVST cases were asymptomatic. Male (84% vs. 52%, p = 0.008), immune subtype of T (37% vs. 10%, p = 0.001) and higher initial platelet counts (196.25 ± 140.67 vs. 112.49 ± 115.62, p = 0.02) patients were more likely to develop CVST. The common symptoms were headache (56%), seizures (31%), vomiting (13%), lethargy (13%), coma (6%), hallucinations (6%), and schizophrenia (6%). Symptomatic patients had a higher likelihood of transverse sinus involvement (75% vs. 9%, p = 0.006). Asymptomatic patients had shorter treatment durations (25.5 ± 16.7 weeks vs. 51.6 ± 25.8 weeks, p = 0.02) and fewer long-term complications (50% vs. 0%, p = 0.02). Thromboelastographic amplitude values at 30 minutes after maximum amplitude were significantly higher in symptomatic patients (49.4 ± 13.2 vs. 35.1 ± 8.3, p = 0.01). This study highlights a significant incidence of PEG-ASP-related CVST in children, with MRV screening revealing a notably higher detection rate than previously reported. Most cases were asymptomatic, which demonstrated better prognoses, emphasizing the importance of MRV for early CVST diagnosis after induction remission in ALL/LBL.

Keywords

pegasparaginase - cerebral venous sinus thrombosis - magnetic resonance venography - acute lymphoblastic leukemia - lymphoblastic lymphoma

^* These authors contributed equally and share the first authorship.

Publication History

Received: 09 December 2024

Accepted: 04 April 2025

Article published online:
25 April 2025

• References

• 1 Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev 2010; 36 (04) 277-285
• 2 Gatta G, Botta L, Rossi S. et al; EUROCARE Working Group. Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5–a population-based study. Lancet Oncol 2014; 15 (01) 35-47
• 3 Cooperation Group of Phase II Clinical Trial of PEG-Asp. Comparison of polyethylene glycol conjugated asparaginase and L-asparaginase for treatment of childhood acute lymphoblastic leukemia. Zhonghua Xue Ye Xue Za Zhi 2008; 29 (01) 29-33
• 4 Mitchell L, Hoogendoorn H, Giles AR, Vegh P, Andrew M. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L'Asparaginase-induced antithrombin III deficiency. Blood 1994; 83 (02) 386-391
• 5 Andrew M, Brooker L, Mitchell L. Acquired antithrombin III deficiency secondary to asparaginase therapy in childhood acute lymphoblastic leukaemia. Blood Coagul Fibrinolysis 1994; 5 (Suppl. 01) S24-S36 , discussion S59–S64
• 6 Couturier MA, Huguet F, Chevallier P. et al. Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: the GRAALL experience. Am J Hematol 2015; 90 (11) 986-991
• 7 Ranta S, Tuckuviene R, Mäkipernaa A. et al. 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 (04) 547-552
• 8 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
• 9 Arber DA, Orazi A, Hasserjian R. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20) 2391-2405
• 10 Ferro JM, Bousser MG, Canhão P. et al; European Stroke Organization. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis - endorsed by the European Academy of Neurology. Eur J Neurol 2017; 24 (10) 1203-1213
• 11 Saposnik G, Bushnell C, Coutinho JM. et al; American Heart Association Stroke Council; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke Nursing; and Council on Hypertension. Diagnosis and management of cerebral venous thrombosis: a scientific statement from the American Heart Association. Stroke 2024; 55 (03) e77-e90
• 12 Musgrave KM, van Delft FW, Avery PJ. et al. Cerebral sinovenous thrombosis in children and young adults with acute lymphoblastic leukaemia - a cohort study from the United Kingdom. Br J Haematol 2017; 179 (04) 667-669
• 13 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
• 14 Coutinho JM, Ferro JM, Canhão P. et al. Cerebral venous and sinus thrombosis in women. Stroke 2009; 40 (07) 2356-2361
• 15 Schaller B, Graf R. Cerebral venous infarction: the pathophysiological concept. Cerebrovasc Dis 2004; 18 (03) 179-188
• 16 Saposnik G, Barinagarrementeria F, Brown Jr RD. et al; American Heart Association Stroke Council and the Council on Epidemiology and Prevention. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42 (04) 1158-1192
• 17 Lauw MN, Van der Holt B, Middeldorp S, Meijers JC, Cornelissen JJ, Biemond BJ. Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: effect of fresh frozen plasma supplementation. Thromb Haemost 2013; 109 (04) 633-642
• 18 Ghanem KM, Dhayni RM, Al-Aridi C. et al. Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: risk factors and management. Pediatr Blood Cancer 2017; 64 (12) e26694
• 19 Lalive PH, de Moerloose P, Lovblad K, Sarasin FP, Mermillod B, Sztajzel R. Is measurement of D-dimer useful in the diagnosis of cerebral venous thrombosis?. Neurology 2003; 61 (08) 1057-1060
• 20 Kosinski CM, Mull M, Schwarz M. et al. Do normal D-dimer levels reliably exclude cerebral sinus thrombosis?. Stroke 2004; 35 (12) 2820-2825