Cerebral Venous Thrombosis As a Complication of Treatment for Acute Lymphoblastic Leukaemia in Children and Young Adults

Cerebral venous thrombosis (CVT) is a significant complication of therapy in children and young adults with acute lymphoblastic leukaemia (ALL). Previous reports indicate a considerable risk of mortality and morbidity in relation to CVT. In addition, there is potential for suboptimal treatment of ALL due to avoidance of Asparaginase and the need for reversal of anticoagulant therapy for invasive procedures such as intrathecal chemotherapy. Anticoagulation may be complicated by haemorrhage.

This retrospective study aimed to identify the clinical features, therapy and outcome of CVT occurring during treatment of ALL in individuals, aged 1 to 24 years, who participated in the Medical Research Council UK ALL 2003 (MRC UKALL 2003) randomised controlled trial.

Cases of CVT were identified from adverse event reporting. All reports were screened for central nervous system thrombosis and grade 4 serious adverse events in the category of coagulation/thrombosis. Reporting centres were asked for additional clinical information.

3126 children and young adults were enrolled in the study between 2003 and 2011, with median age 5 years, including 1776 males (56.8%). The 3 initial treatment regimens: A, B and C: corresponded to standard-risk, intermediate-risk and high-risk, respectively. 55% were treated with regimen A, 32% regimen B and 13% regimen C. 48 individuals (1.5%) developed CVT and data were returned for 42. Median age was 10 (range: 1 to 18) years and 25 cases were male (59.5%). 71.4% of cases (30/42) occurred during induction therapy. 18 cases were in individuals treated with regimen A, 22 regimen B and 2 regimen C. Median time between the most recent Asparaginase dose and CVT was 12.5 days (range: 1-111 days). 29 cases (68.4%) had received 2 doses of Asparaginase prior to thrombosis, 5 cases >2 doses and 8 cases 1 dose.

Presenting symptoms were: seizures, 22 cases (52.3%); neurological impairment, 20 (47.6%); headache, 19 (45.2%); reduced conscious level, 8 (19.0%); nausea/vomiting, 8 (19.0%). Identified thrombotic risk factors included: hospitalisation, 22 (52.3%); active infection, 5; recent immobility, 5; dehydration, 6; combined oral contraceptive pill, 2. None were obese, had a high white cell count at time of CVT diagnosis or a history of recent major surgery. 13 (31.0%) had >1 thrombotic risk factor and 16 (38.1%) had no additional clinical risk factor identified. 10 had a thrombophilia screen performed, one with a repeatedly low protein S level (male, 1 year of age). 7 cases (16.7%) had cerebral infarction on imaging and 11 (26.2%) were complicated by intracranial haemorrhage (ICH).

38 cases (90.5%) received anticoagulant therapy, 37 of which received low molecular weight heparin (LMWH) and one unfractionated heparin. One case had catheter-directed thrombolysis. 4 were not anticoagulated, 3 due to ICH. 2 received Antithrombin replacement therapy. Anticoagulation therapy was continued for a median of 3 months. 65.0% of cases due more Asparaginase were re-exposed (26/40), 19 of which received thromboprophylaxis during re-exposure. 2 remain on long-term therapeutic anticoagulation. In 23 cases (54.8%) CVT resulted in a delay or change to planned treatment.

Neurological morbidity was reported in 4 cases (9.5%): seizure disorder, 2; hemiplegia, 1; residual hemiplegia and hemianopia with severe developmental delay, 1. 36 cases (85.7%) remain in first remission. Survival in those with CVT was 90.1%, comparable to actuarial 5-year survival of the entire cohort (91.5%). There were 4 deaths, three due to leukaemia (two in first relapse) and one due to pneumonia as a complication of stem cell transplant. There were no deaths due to CVT or bleeding on anticoagulant therapy.

This study highlights the clinical features of CVT in children and young adults treated for ALL in the MRC UKALL 2003 trial, in particular the timing in relation to Asparaginase treatment, presenting features and neurological outcome. These data support LMWH as safe treatment for CVT in this clinical setting. We have demonstrated the tendency of clinicians to adjust treatment regimen and/or avoid further Asparaginase exposure in response to CVT. However, overall survival at 5 years did not differ for the cohort with CVT. Future studies should aim to further evaluate clinical predictors, alongside potential coagulation and genetic markers, in order to identify a high-risk group that may benefit from measures to reduce CVT during ALL therapy.