Evaluation of Dexamethasone Versus Prednisone in Induction Therapy for Pediatric and Adolescent Lymphoblastic Lymphoma: A Randomized Controlled Trial

The primary objective of this study is to evaluate the efficacy of substituting **prednisone** with **dexamethasone** in induction therapy for patients with lymphoblastic lymphoma (LBL). This substitution aims to decrease the cumulative incidence of relapses in the central nervous system (CNS). Additionally, for high-risk patients, the study seeks to determine if an intensified treatment regimen can improve the probability of event-free survival (pEFS) compared to the standard treatment arm. These objectives are clinically relevant as they address the potential to reduce CNS relapses and improve survival outcomes in LBL, which are critical factors in the management of this aggressive malignancy.

Secondary objectives include: - Comparing pEFS and the cumulative incidence of relapse/CNS-relapse with the EURO-LB 02 study. - Assessing overall survival (pOS) from diagnosis to death or last contact. - Evaluating treatment-related mortality in randomized arms. - Analyzing adverse event profiles in specific protocol elements or randomized arms. - Investigating the feasibility and results of risk group stratification. - Evaluating the feasibility of minimal residual disease (MRD) assessment in children and adolescents with LBL. - Identifying prognostic molecular markers for T-cell lymphoblastic lymphoma (T-LBL) that could enhance risk group stratification in future trials.

The clinical trial involves a total of **15 participants** diagnosed with **lymphoblastic lymphoma**. The study population includes both male and female subjects under the age of 18, reflecting a pediatric cohort. Participants were selected based on their recent diagnosis of lymphoblastic lymphoma and enrollment in a participating center. The trial includes a vulnerable population, as it involves minors. All participants have provided written informed consent, either personally if over 14 years of age or through their parents, in accordance with local laws and regulations. The study does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include the willingness of patients and investigators to provide necessary samples for pathology and genetic risk group stratification, if available post-standard diagnostic procedures.

The clinical trial is designed to evaluate the efficacy and safety of treatment protocols for children and adolescents diagnosed with **lymphoblastic lymphoma**. This is a Phase III, randomized, double-blind, controlled trial aimed at confirming the safety and efficacy of the treatment. The trial is expected to run from August 23, 2019, to November 22, 2027, with the primary objective of reducing the cumulative incidence of central nervous system relapses and improving event-free survival probabilities in high-risk patients.

Participants will be randomly assigned to either the standard treatment arm or the experimental treatment arm. The standard arm involves the administration of **prednisone** at a dose of 60 mg/m²/day for 21 days with a 9-day tapering period. The experimental arm substitutes **prednisone** with **dexamethasone** at a dose of 10 mg/m²/day for 14 days without tapering. High-risk patients in the experimental arm will receive additional doses of **PEG-asparaginase** and an intensified treatment protocol.

The trial includes several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age under 18 years, newly diagnosed condition, and consent to participate. Follow-up visits will be scheduled to monitor treatment response and adverse events. The end-of-study visit will assess the primary and secondary endpoints, including the incidence of CNS relapse and event-free survival rates.

Participant involvement is expected to last up to 84 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or non-compliance with the study protocol. The trial is conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, routes, and frequencies of administration. **Prednisolone** is administered intrathecally with a maximum daily dose of 10 mg and a total dose of 240 mg over a treatment period of 24 days. **Tioguanine** is given orally with a maximum daily dose of 60 mg/m² and a total dose of 840 mg/m² over 14 days. **Pegaspargase** is administered intravenously with a maximum daily dose of 3750 IU and a total dose of 18750 IU over 5 days. **Cytarabine** is also administered intravenously, with a maximum daily dose of 4000 mg/m² and a total dose of 5800 mg/m² over 25 days.

**Daunorubicin** is administered intravenously with a maximum daily dose of 30 mg/m² and a total dose of 150 mg/m² over 5 days. **Prednisone** is administered both intravenously and orally, with a maximum daily dose of 60 mg/m² and a total dose of 1837.5 mg/m² over 37 days. **Doxorubicin hydrochloride** is administered intravenously with a maximum daily dose of 30 mg/m² and a total dose of 120 mg/m² over 4 days. **Ifosfamide** is administered intravenously with a maximum daily dose of 1600 mg/m² and a total dose of 4000 mg/m² over 3 days.

**Cyclophosphamide** is administered intravenously with a maximum daily dose of 1000 mg/m² and a total dose of 4000 mg/m² over 6 days. **Vindesine sulfate** is administered intravenously with a maximum daily dose of 5 mg and a total dose of 10 mg over 2 days. **Vincristine** is administered intravenously with a maximum daily dose of 2 mg and a total dose of 20 mg over 10 days. **Dexamethasone acetate** is administered both intravenously and orally, with a maximum daily dose of 20 mg/m² and a total dose of 576.25 mg/m² over 54 days.

**Mercaptopurine** is administered orally with a maximum daily dose of 60 mg/m² and a total dose of 3080 mg/m² over 84 days. **Methotrexate sodium** is administered intravenously with a maximum daily dose of 5 gm/m² and a total dose of 20 gm/m² over 4 days. Each medication is of chemical origin, except for Pegaspargase, which is of biological/biotechnological origin. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules.

The efficacy of the clinical trial will be assessed through the evaluation of primary endpoints associated with the treatment of lymphoblastic lymphoma in children and adolescents. The primary endpoints for the first randomized question (R1) include the **cumulative incidence of relapse** with involvement of the central nervous system (CNS-relapse, pCICR). For the second randomized question (R2), the primary endpoint is the estimated probability of **event-free survival** (pEFS). These endpoints are critical in determining the effectiveness of the treatment protocols being tested.

The trial involves two arms: a standard arm (SA) and an experimental arm (EA). In the SA, patients receive prednisone, while in the EA, dexamethasone is administered during induction therapy. The efficacy will be measured by comparing the outcomes between these two arms. The trial is designed to test whether substituting prednisone with dexamethasone can decrease the incidence of CNS relapses and whether an intensified treatment regimen can improve pEFS in high-risk patients. The trial is structured to provide robust data on the efficacy of these treatment modifications, with the ultimate goal of improving patient outcomes in lymphoblastic lymphoma.