Title: Role of primary VTE prophylaxis in pediatric leukemia, lymphoma, and solid tumors: A systematic review and meta-analysis.

Abstract Background/ introduction: Venous thromboembolism (VTE) is an increasingly recognized cause of morbidity in children, particularly among those who are hospitalized or have chronic illnesses. Pediatric patients with lymphoblastic leukemia/ lymphoma or solid tumors are at especially high risk. This systematic review and meta-analysis aims to evaluate the effectiveness of primary anticoagulant prophylaxis in preventing VTE among children diagnosed with lymphoblastic leukemia, lymphoma, or solid tumors. Methods As part of the American Society of Hematology (ASH) and the International Society of Thrombosis and Haemostasis (ISTH) guidelines on anticoagulant prophylaxis for pediatric VTE prevention, we searched the published literature in PubMed, Embase, and The Cochrane Central Register of Controlled Trials, from inception till April 2025. Two reviewers independently screened the studies to assess their eligibility using Covidence systematic review software (Australia). A study was included if it included any of the primary outcomes of interest and where the population of interest, children with lymphoblastic leukemia/ lymphoma or solid tumors, including Hodgkin's lymphoma, had received a prophylactic dose of anticoagulation for primary prevention. We statistically combined estimates using RevMan web using the random effect model. Reviewers assessed the risk of bias using the Cochrane Risk of Bias 2 (RoB 2) tool for randomized controlled trials, and the Risk of Bias in Non-randomized Studies - of Interventions (ROBINS-I) tool for nonrandomized studies of intervention. Reviewers assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results After screening 13289, we included 5 studies assessing the use of primary pharmacological prophylaxis in pediatric patients with leukemia/ lymphoblastic lymphoma and 4 studies assessing the use of primary prophylaxis in those with solid tumors, including Hodgkin's lymphoma. For primary anticoagulant prophylaxis in pediatric patients with leukemia/ lymphoblastic lymphoma, two randomized controlled trials and four 3 non-randomized studies of interventions were included. All-cause mortality was informed by one RCT that showed RR of 0.25 (95% CI: 0.03 to 22.22) in those receiving prophylaxis, corresponding to an absolute of 12 fewer per 1000 (from 15 fewer to 332 more). For overall thromboembolic events, two RCTs showed RR of 0.73 (95% CI: 0.44 to 1.24) in the prophylaxis arm, which corresponds to an absolute of 39 fewer per 1,000 (from 80 fewer to 34 more). For symptomatic VTE, the relative risk was 0.48 (95% CI 0.26 to 0.87), equating to 28 fewer per 1,000 receiving prophylaxis (from 40 fewer to 7 fewer). For major bleeding, the RR was 0.66 (95% CI: 0.16 to 2.76), corresponding to 3 fewer per 1,000 (from 8 fewer to 17 more). The overall certainty of evidence was very low due to concerns over risk of bias, inconsistency, and imprecision. Across the assessed outcomes in NRSIs, the relative risk (RR) for overall VTE was 0.16 (95% CI: 0.02 to 1.22), translating to 49 fewer events per 1,000 patients (ranging from 58 fewer to 13 more). For symptomatic VTE, the RR was 0.17 (95% CI: 0.03 to 1.11), corresponding to 604 fewer events per 1,000 patients (from 705 fewer to 80 more). No major bleeding events were reported in either group, but the results were not pooled due to sparse data. Across all outcomes, the certainty of evidence was very low due to concerns about risk of bias and imprecision. For anticoagulant prophylaxis in pediatric patients with solid tumors, including Hodgkin's lymphoma, four NRSIs were included. The included studies showed that prophylaxis might be associated with a lower incidence of VTE events compared with no prophylaxis (RR 0.03 95% CI 0.03 to 0.09), corresponding to 30 more per 1,000 (from 30 fewer to 90 more). The incidence of symptomatic VTE might be lower when using primary prophylaxis with a RR of 0.01(95% CI 0.03 to 0.05), corresponding to 10 more per 1,000 (from 30 fewer to 50 more). None of the captured studies have reported on all-cause mortality or bleeding. The overall certainty of evidence is low due to concerns about risk of bias and imprecision. Conclusion The findings of this systematic review underscore the need for high-quality randomized controlled trials to better define the balance of benefits and harms of primary VTE prophylaxis in pediatric population with malignancy.