Evaluation of Rituximab and Chemotherapy Regimens in Pediatric Aggressive B-cell Lymphoma and Leukemia: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **event-free survival** (EFS) in pediatric patients with mature aggressive B-cell lymphoma and leukemia. Specifically, the study aims to assess EFS in patients with very limited B-NHL (R1 and R2 stage I and II) by substituting anthracyclines with a rituximab window without compromising survival rates. Additionally, it seeks to determine EFS in patients with limited B-NHL (R2 stage III) who are randomly assigned to receive rituximab plus standard chemotherapy (S-CTX) or S-CTX without rituximab. For patients with advanced B-NHL/B-AL (R3 and R4 including R4 CNS+), the study will compare EFS and immune reconstitution (IR) between those treated with BFM-type chemotherapy and those receiving one versus seven doses of rituximab. The clinical relevance of these objectives lies in optimizing treatment regimens to improve survival outcomes while minimizing treatment-related toxicity in children and adolescents.

Secondary objectives include analyzing:

• Event-free survival, overall survival, and immune reconstitution across various subgroups such as histology, CNS status, gender, age, risk group, CD19+ count, and immunoglobulin levels prior to treatment.
• Additional parameters for immune reconstitution, including lymphocyte subpopulations, immunoglobulin levels, and grade III/V infections at 6, 12, 18, and 24 months post-treatment, with continued 6-monthly assessments until normalization.
• The rate of patients achieving sufficient titers after vaccination one year post-treatment.
• The effect of one versus seven doses of rituximab on the adverse event (AE) and serious adverse event (SAE) profile in randomized arms of R3/R4 patients.

The clinical trial involves a total of **45 participants** diagnosed with **mature aggressive B-cell lymphoma and leukemia** in children and adolescents. The study population includes both male and female subjects under the age of 18, with a focus on newly diagnosed cases. Participants were selected based on specific criteria, including histological or cytological and immunological confirmation of aggressive mature B-cell Non-Hodgkin lymphoma, such as Burkitt lymphoma, Burkitt leukemia, or diffuse large B-cell lymphoma. The trial requires participants to have adequate hepatic, renal, and cardiac function unless alterations are due to lymphoma infiltration. Additionally, participants must not have received previous chemotherapy or lymphoma-directed treatment, and steroid use is limited to no more than two days in the last month. Lifestyle considerations such as diet and physical activity are not specified, but participants must have a certificate of vaccination against hepatitis B or a negative serology. The trial includes a vulnerable population, and informed consent is required from patients or their guardians. The study aims to analyze event-free survival and immune reconstitution in pediatric patients, with a follow-up period of at least two years after the initial diagnosis.

The clinical trial is designed to evaluate the efficacy and safety of various treatment regimens for **mature aggressive B-cell lymphoma and leukemia** in pediatric patients. This is a Phase III, randomized, double-blind, controlled trial aimed at confirming the safety and efficacy of the treatment protocols. The trial is expected to run from August 21, 2017, to June 20, 2027, with an estimated duration of 10 years. Participants will be involved in the study for a period that aligns with their specific treatment regimen, which may vary depending on the stage and classification of their condition.

The trial involves several key study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and organ function. Following the screening, participants will be randomized into different treatment arms. The trial includes multiple follow-up visits to monitor the participants' response to treatment, assess event-free survival (EFS), and evaluate immune reconstitution. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment outcomes.

Participants are expected to adhere to the study protocol throughout the trial duration. However, conditions such as non-response, progressive disease, or adverse events may lead to early termination from the study. The primary endpoints include EFS and immune reconstitution rate, with secondary endpoints focusing on safety and long-term outcomes. The trial aims to provide valuable insights into optimizing treatment strategies for this patient population, ensuring that the findings contribute to improved clinical practices.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Cytarabine** is administered intrathecally with a maximum daily dose of 30 mg and a total dose of 450 mg over a treatment period of 15 days. The pharmaceutical form is coded as PHF00230MIG. **Vinblastine sulfate** is given intravenously with a maximum daily dose of 2 mg and a total dose of 8 mg over 4 days, in the pharmaceutical form PHF675.

**Ifosfamide** is administered intravenously with a maximum daily dose of 1600 mg/m² and a total dose of 8000 mg/m² over 6 days, in the pharmaceutical form PHF00231MIG. **Abiraterone acetate** is administered intrathecally with a maximum daily dose of 10 mg and a total dose of 150 mg over 15 days, in the pharmaceutical form PHF00082MIG. **Methotrexate** is administered intrathecally with a maximum daily dose of 12 mg and a total dose of 180 mg over 15 days, in the pharmaceutical form PHF00230MIG.

**Vindesine sulfate** is administered intravenously with a maximum daily dose of 5 mg and a total dose of 10 mg over 2 days, in the pharmaceutical form PHF00231MIG. **Etoposide** is administered intravenously with a maximum daily dose of 200 mg/m² and a total dose of 1400 mg/m² over 10 days, in the pharmaceutical form PHF675. **Dexamethasone acetate** is administered intravenously with a maximum daily dose of 20 mg/m² and a total dose of 480 mg/m² over 39 days, in the pharmaceutical form PHF00245MIG.

**Anhydrous cyclophosphamide** is administered intravenously with a maximum daily dose of 400 mg/m² and a total dose of 2400 mg/m² over 8 days, in the pharmaceutical form PHF00231MIG. **Rituximab** is administered intravenously with a maximum daily dose of 375 mg/m² and a total dose of 2625 mg/m² over 7 days, in the pharmaceutical form PHF00230MIG. **Doxorubicin** is administered intravenously with a maximum daily dose of 25 mg/m² and a total dose of 100 mg/m² over 4 days, in the pharmaceutical form PHF00231MIG.

Each medication is of chemical origin, except for rituximab, which is a protein-based treatment. Participant compliance is monitored through adherence to the dosing schedules and administration routes as specified. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy and safety of these experimental medications in the treatment of mature aggressive B-cell lymphoma and leukemia in children and adolescents.

The efficacy of the clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)**. This parameter is defined as the time from the start of treatment or randomization to the occurrence of an event or the date of the last contact for patients without an event. Events are characterized by non-response, progressive disease or relapse, treatment-related death, death from any other cause, or the diagnosis of secondary malignancies. For patients with stage I and II B-cell Non-Hodgkin lymphoma (B-NHL), the primary endpoint is EFS from the start of treatment. For stage III B-NHL patients, EFS is measured from the point of randomization. In patients with advanced B-NHL/B-acute leukemia (B-AL), EFS is evaluated from both the start of treatment and randomization.

Additionally, the trial will assess the **immune reconstitution rate**, which is the percentage of patients achieving age-adjusted normal B-cell counts (CD19+ subpopulations) 12 months after the start of treatment. This secondary efficacy parameter will provide insights into the recovery of the immune system following treatment. The trial will employ a randomized design to compare the efficacy of different treatment regimens, including the use of rituximab in varying doses, to determine if the addition of rituximab can improve EFS and whether a single dose is sufficient for the intended improvement. The analysis will be conducted at specified time points to ensure comprehensive evaluation of the treatment's efficacy over the course of the trial.