Additive and Dose-Dependent Effect of Rituximab on ‎Pediatric ‎Patients’ Outcomes Concurrently Receiving Immunosuppressive ‎Chemotherapy, A Prospective Cohort Study

Background: Rituximab (RTX) is approved for treating CD20-positive B-cell malignancies, including non-Hodgkin lymphoma, when used alongside chemotherapy. It has the potential to interact with and alter the host immune system, putting patients at a heightened risk of infection. Therefore, the use of RTX necessitates a meticulous assessment of infectious risks based on the latest evidence. Objectives: We conducted a prospective investigation into infectious complications and mortality among children undergoing RTX treatment over the observation period of the study. Methods: In this observational cohort study, we included 61 pediatric patients treated with RTX for malignancy and immune thrombocytopenic purpura (ITP), as well as 122 cancer patients who had never received RTX (the unexposed group). These patients were prospectively monitored for febrile neutropenia (FN), bloodstream infection (BSI), invasive fungal infection (IFI), and mortality. All infectious complications were documented starting from the initial dose of RTX and continuing for at least six months following the last dose. Logistic regression and Cox regression analyses, with consideration for the proportional hazards assumption, were utilized to evaluate the impact of covariates on mortality and infection-related outcomes. Results: Infectious complications were observed in 52.5% of children treated with RTX. These complications were notably more prevalent in children with malignancy compared to those with chronic ITP (89.5% versus 10.5%, respectively). RTX was found to be associated with an increased likelihood of mortality in children with malignancy (OR [95% CI]: 1.54 [0.41, 5.69]). According to Cox regression analysis, RTX was linked to a higher risk of IFIs, death, FN events, and BSIs over a 36-month observation period (4.33 [1.21, 15.52], 3.26 [1.008, 10.59], 1.68 [0.83, 3.41], and 1.59 [0.27, 9.17], respectively). The total dose of RTX administered was also associated with adverse patient outcomes, with the odds of infectious events and death increasing in the second, third, and fourth quartiles of the total RTX dose administered. Furthermore, the estimated one-year and two-year survival rates for cancer patients treated with RTX were 77% and 58%, respectively. Conclusions: RTX treatment, when used concurrently with immunosuppressive chemotherapy for hematologic malignancies in children, showed additive and dose-dependent effects on clinical outcomes.