Evaluation of Non-Total Body Irradiation Conditioning Regimens with Fludarabine, Thiotepa, and Busulfan in Pediatric Acute Lymphoblastic Leukemia Transplantation

The primary objective of the study titled "ALL SCTped 2012 FORUM - Allogeneic Stem Cell Transplantation in Children and Adolescents with **Acute Lymphoblastic Leukaemia**" is to evaluate the survival outcomes of non-total body irradiation (TBI) conditioning regimens compared to TBI/Etoposide in children older than 4 years undergoing hematopoietic stem cell transplantation (HSCT) from a Human Leukocyte Antigen (HLA) identical sibling donor or an HLA matched donor. This is clinically relevant as it aims to determine if non-TBI regimens can provide similar survival benefits while potentially reducing the long-term adverse effects associated with TBI.

Additional objectives include exploring the impact of risk factors on the incidence of adverse events of special interest and overall survival in the entire cohort, particularly in children aged 2-4 years receiving TBI/VP16 conditioning. Furthermore, the study aims to assess event-free survival after HSCT from HLA mismatched donors, including mismatched unrelated donors, mismatched cord blood, or HLA haplo-identical family members.

The clinical trial involves a total of **450 participants** diagnosed with **Acute Lymphoblastic Leukaemia** (ALL), excluding those with mature B-ALL. The study population includes both male and female subjects, with an age range at diagnosis of up to 18 years or up to 21 years at the time of hematopoietic stem cell transplantation (HSCT). Participants were selected based on their indication for allogeneic HSCT and must have achieved complete remission before the transplantation. The trial does not include pregnant individuals, those with secondary malignancies, or those who have undergone previous HSCT. Participants are required to provide written consent, either from their legal guardians or themselves if they are minors. The study does not focus on a vulnerable population, and all HSCT procedures are conducted at participating centers. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed to evaluate the efficacy and safety of various conditioning regimens in children and adolescents with **Acute Lymphoblastic Leukaemia** undergoing allogeneic stem cell transplantation. The trial employs a randomized, controlled, and double-blind methodology to ensure unbiased results. The study is divided into two strata, each with specific objectives and endpoints. Stratum 1 focuses on comparing non-total body irradiation (TBI) conditioning regimens with TBI/Etoposide, while Stratum 2 explores event-free survival after transplantation from HLA mismatched donors. The trial is expected to conclude by June 2030, with recruitment having commenced in April 2013.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as age, remission status, and consent. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall survival. The end-of-study visit will assess long-term outcomes and any late-onset effects. The expected duration of participant involvement varies depending on the treatment regimen, with the maximum treatment period extending up to 28 days for certain medications like **blinatumomab**.

Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the protocol, or if the investigator deems it necessary for their safety. The trial's primary endpoints include overall survival for Stratum 1 and event-free survival for Stratum 2. Secondary endpoints encompass cumulative incidence of treatment-related mortality, relapse, and both acute and chronic graft-versus-host disease. The trial aims to provide comprehensive data on the safety and efficacy of the conditioning regimens, contributing to improved treatment strategies for pediatric patients with Acute Lymphoblastic Leukaemia.

The clinical trial involves the administration of several **experimental medications**. **Etoposide** is provided as a concentrate for solution for infusion, with a maximum daily dose of 60 mg/kg and a total dose of 60 mg/kg. It is administered intravenously over a treatment period of one day. **Treosulfan** is supplied as a powder for solution for infusion, with a maximum daily dose of 14,000 mg/m² and a total dose of 42,000 mg/m², administered intravenously over three days. **Thiotepa** is available as a powder for concentrate for solution for infusion, with a maximum daily and total dose of 10 mg/kg, administered intravenously over one day.

**Cyclophosphamide** is provided as a powder for solution for injection/infusion, with a maximum daily dose of 60 mg/kg and a total dose of 120 mg/kg, administered intravenously over two days. **Busulfan** is available as a concentrate for solution for infusion, with a maximum daily dose of 4.8 mg/kg and a total dose of 19.2 mg/kg, administered intravenously over four days. **Blinatumomab** is supplied as a solution for infusion, with a maximum daily dose of 28 µg/m² and a total dose of 784 µg/m², administered intravenously over 28 days.

**Rabbit anti-human thymocyte immunoglobulin** is provided as a powder for solution for infusion, with a maximum daily dose of 2.5 mg/kg and a total dose of 7.5 mg/kg, administered intravenously over three days. **Anti-human T-lymphocyte immunoglobulin from rabbits** is available as a concentrate for solution for infusion, with a maximum daily dose of 15 mg/kg and a total dose of 45 mg/kg, administered intravenously over three days. **Fludarabine phosphate** is supplied as a concentrate for solution for infusion, with a maximum daily dose of 30 mg/m² and a total dose of 150 mg/m², administered intravenously over five days.

All medications are of chemical origin, except for blinatumomab, which is a protein-based treatment. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance is monitored through adherence to the dosing schedules and administration routes specified for each medication. The trial aims to evaluate the efficacy and safety of these treatments in the context of allogeneic stem cell transplantation in children and adolescents with acute lymphoblastic leukemia.

The efficacy of the clinical trial will be assessed using specific **endpoints**. The primary endpoints include Overall Survival (OS) for Stratum 1 and Event Free Survival (EFS) for Stratum 2. Secondary endpoints encompass EFS for Stratum 1, OS for Stratum 2, and several other parameters applicable to both strata. These include the Cumulative Incidence of Treatment-related Mortality (TRM), Cumulative Incidence of Relapse, and assessments of Toxicity, both acute and late. Additionally, the occurrence of Acute Graft versus Host Disease (aGVHD) and chronic GVHD (cGvHD), as well as the incidence of secondary malignancies, will be evaluated.

The trial will involve the administration of various medicinal products, including **ETOPOSIDE**, **TREOSULFAN**, **THIOTEPA**, **CYCLOPHOSPHAMIDE**, **BUSULFAN**, **BLINATUMOMAB**, **RABBIT ANTI-HUMAN THYMOCYTE IMMUNOGLOBULIN**, **ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS**, and **FLUDARABINE PHOSPHATE**. These products will be administered intravenously, with specific dosing regimens and maximum treatment periods defined for each. The trial aims to explore the impact of these treatments on survival rates and the incidence of adverse events in children and adolescents with Acute Lymphoblastic Leukemia (ALL) undergoing allogeneic stem cell transplantation.