Evaluation of PEGaspargase and Rituximab in Pediatric Non-Mature-B Acute Lymphoblastic Leukemia: A Randomized Clinical Trial

The primary objective of the study is to enhance the **event-free survival (EFS)** probability in children diagnosed with acute lymphoblastic leukemia (ALL). This objective is clinically significant as improving EFS can lead to better long-term outcomes and reduced relapse rates in pediatric patients with ALL.

Secondary objectives include:

• Improving risk group definition by enhancing genetic studies at diagnosis and incorporating minimal residual disease (MRD) determinations on days 33 and 78 using flow cytometry.
• Reducing mortality rates during the induction phase and in complete remission.
• Evaluating the role of intensified treatment with **PEG-asparaginase**.
• Assessing the impact of immunotherapy, specifically anti-CD20, in patients with B-cell precursor ALL (Bcp-ALL).

The clinical trial involves a total of **600 participants** diagnosed with **Childhood non-mature-B Acute Lymphoblastic Leukemia**. The study population includes both male and female subjects, with an age range from 1 to less than 18 years. Participants were selected based on specific inclusion criteria, including the requirement for the start of induction therapy within the designated enrollment period from December 1, 2022, to December 31, 2028. The trial population is characterized by a vulnerable group, given the pediatric nature of the condition. General health status considerations include the necessity for a negative urine βHCG test in female patients with childbearing potential. The trial aims to improve survival rates and reduce morbidity and mortality among children with this condition, while also exploring new treatment strategies. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of treatment strategies for **Childhood non-mature-B Acute Lymphoblastic Leukemia**. This trial is a randomized, double-blind, controlled study aimed at improving survival rates and reducing morbidity and mortality among pediatric patients. The trial will assess the impact of intensified treatment with **pegaspargase** and the role of immunotherapy using **rituximab**. The study is expected to run from December 1, 2022, to December 31, 2035, with recruitment starting on September 1, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (1 to <18 years), diagnosis of acute lymphoblastic leukemia (ALL), and informed consent. The trial will include multiple follow-up visits to monitor treatment response and safety, with key assessments on day 33 and day 78 to evaluate minimal residual disease (MRD) status. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events.

The expected length of participant involvement is up to 80 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include non-response after the HR2 consolidation block, relapse, second malignancy, or death from any cause. The primary endpoint is the event-free survival (EFS) time, while secondary endpoints include overall survival time, safety of rituximab in combination with intensive chemotherapy, and additional research on CD20 expression and monoclonal antibody therapy response.

The clinical trial involves the administration of **Oncaspar**, a **PEGASPARGASE** formulation, which is provided as a **powder for solution for injection/infusion**. The pharmaceutical form is specifically designed for infusion, ensuring precise delivery of the active substance. The maximum daily dose of Oncaspar is 2500 units, with a total maximum dose of 27500 units over the treatment period. The administration route is via infusion, and the treatment duration is capped at 22 weeks. The product is manufactured by Les Laboratoires Servier and is not a pediatric formulation. Participant compliance is monitored through scheduled dosing and infusion protocols to ensure adherence to the treatment regimen.

Additionally, the trial includes the use of **Riximyo**, which contains the active substance **RITUXIMAB**. This medication is provided as a **concentrate for solution for infusion**. The maximum daily dose is 750 mg, with a total maximum dose of 4500 mg over the course of the treatment, which extends up to 80 weeks. Riximyo is administered via infusion, and the product is manufactured by Sandoz GmbH. Similar to Oncaspar, Riximyo is not formulated for pediatric use. The trial protocol includes detailed infusion schedules and monitoring to ensure participant compliance and accurate dosing throughout the study period.

Efficacy in the clinical trial for the management of childhood non-mature-B **Acute Lymphoblastic Leukemia** (ALL) will be assessed using several primary and secondary endpoints. The primary endpoint is the minimum time from randomization until the first event, which includes non-response after HR2 consolidation block, relapse, second malignancy, or death from any cause, referred to as Event-Free Survival (EFS) time. Secondary endpoints include the time to death from any cause measured from the time of randomization, and the status of Minimal Residual Disease (MRD) at the end of induction (day 33) and end of early intensification (day 78).

Additional secondary endpoints focus on the safety and efficacy of rituximab in combination with intensive chemotherapy. These include the comparison of death in complete remission (CR) between the two arms, the rate of severe infections (CTC grade 3 to 5) during treatment, and the rate of rituximab infusion reactions. The occurrence of specific infections, such as cytomegalovirus and Herpes zoster, will also be compared, along with the need for immunoglobulin substitution. IgG levels will be measured at day 0 and subsequently at least once monthly until the end of intensive chemotherapy and once every three months during maintenance chemotherapy until normal levels are reached.

Furthermore, the trial will explore the relationship between CD20 expression on ALL blasts at various time points (initially, day 15, day 33, day 78) and the response to monoclonal antibody therapy. It will also assess whether the administration of an anti-B cell monoclonal antibody limits the incidence of peg-asparaginase allergy occurrence. These efficacy parameters will be measured and analyzed at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's impact on patient outcomes.