Alejandra Adriana Cardoso de Castro ^1,2,3 Liana Oliveira ^3,4 Diancarlos Pereira de Andrade ² Edna Kakitani Carbone ^1,3 Roberto Rosati ^2,3,4*

• ¹ Department of Pediatric Oncology and Hematology, Hospital Pequeno Príncipe, Curitiba, Brazil
• ² Faculdades Pequeno Príncipe, Curitiba, Paraná, Brazil
• ³ National Science and Technology Institute for Children’s Cancer Biology and Pediatric Oncology , Federal University of Rio Grande do Sul, Porto Alegre, Rio de Janeiro, Brazil
• ⁴ Pelé Pequeno Príncipe Research Institute, Curitiba, Paraná, Brazil

Objectives: Rituximab is a valuable agent for treating adult B-cell non-Hodgkin lymphoma (B-NHL), and several studies have tested its efficacy in children with mature, high-grade B-NHL. The aim of the present study was to systematically review the use of rituximab in children and adolescents with high-grade mature B-NHL and to conduct a meta-analysis of the evidence. Since access to this medication in public health systems in low-and middle-income countries is complex, we were also interested in mapping access to it in Brazil. Methods: We conducted a systematic review and meta-analysis on the survival of pediatric patients with mature, high-grade and advanced-stage B-NHL treated with rituximab in combination with chemotherapy in first-line treatment or later. Patients' access to the medication was evaluated through a questionnaire sent to oncologists in Brazilian pediatric oncology centers. Results: We selected 17 trials, which were subsequently grouped by disease type and line of therapy. In patients receiving first-line treatment, excluding those with primary mediastinal B-cell lymphoma (PMBL), the use of rituximab resulted in (1) better event-free survival (Hazard Ratio of 0.37 [0.22, 0.61]; p < 0.01); (2) a reduced risk of events (odds ratio of 0.44 [0.26-0.76]; p = 0.003); and (3) a reduced risk of death (odds ratio of 0.44 [0.21-0.89]; p = 0.02). In refractory or relapsed (R/R) patients, rituximab use was associated with a decreased chance of death (odds ratio of 0.25 [0.09-0.75]; p = 0.01). Additionally, our survey included 31 Brazilian centers, 63% of which reported bearing the cost of rituximab. Conclusion: Rituximab improves outcomes in pediatric patients receiving first-line treatment for high-grade B-NHL (except PBML) and overall survival in R/R patients. However, access to rituximab in Brazilian hospitals is currently dependent on centers supporting its economic burden.