Evaluation of Intravenous Busulfan, Fludarabine, and Rabbit Anti-Human Thymocyte Immunoglobulin in Allogeneic Stem Cell Transplantation for High-Risk Myeloid Malignancies

The primary objective of this study is to assess the 2-year **progression-free survival** rates in patients with high-risk myeloid malignancies following hematopoietic stem cell transplantation (HSCT). This is achieved using different dose levels of intravenous Busulfan (BX3 and BX4) combined with fludarabine and thymoglobuline as conditioning therapy. Evaluating progression-free survival is clinically relevant as it provides insight into the efficacy of the conditioning regimen in preventing disease progression, which is crucial for improving long-term outcomes in patients with poor prognosis myeloid malignancies.

Secondary objectives include:

• Documenting full donor **chimerism** achievement, hematologic recovery, and response to treatment rates, which are important for understanding the success of the transplantation and the patient's recovery process.
• Documenting acute and chronic **graft-versus-host disease** (GVHD), relapse, and non-relapse mortality cumulative incidences, which are critical for evaluating the safety and potential complications associated with the transplantation.
• Documenting overall survival, providing a comprehensive measure of the treatment's impact on patient longevity.
• Documenting safety, ensuring that the treatment regimen is tolerable and does not pose undue risk to the patients.

The clinical trial involves participants diagnosed with **high-risk myeloid malignancies**, specifically targeting conditions such as myelodysplastic syndrome and acute myeloid leukemia (AML) beyond the first complete remission (CR1). The study population includes both male and female adults aged 50 to 65 years, as well as those under 50 who are not eligible for myeloablative conditioning regimens. Participants must have a poor prognosis and meet specific criteria, such as the availability of an HLA identical sibling or a matched unrelated donor. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Participants' general health status is not specified, but they must be affiliated with social security and provide written informed consent. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of three different doses of intravenous **busulfan** in combination with **fludarabine** and **thymoglobuline** for conditioning in allogeneic stem cell transplantation (SCT) in patients with high-risk myeloid malignancies. The primary objective is to assess the 2-year progression-free survival rates. The trial is expected to run from March 17, 2014, to March 17, 2026, with participant involvement lasting up to 5 years, depending on individual treatment and follow-up schedules.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and donor availability. Following successful screening, participants will be randomized to receive one of the three dosing regimens. The treatment phase will involve administration of the study drugs via **intravenous infusion** over a period of up to 5 days, depending on the specific regimen. Follow-up visits will be scheduled at regular intervals to monitor safety, efficacy, and any adverse events, with assessments including hematological recovery and donor chimerism achievement at months 1, 2, and 3 post-transplantation.

The end-of-study visit will occur at the conclusion of the follow-up period, where final assessments will be conducted to evaluate the primary and secondary endpoints, including time to progression or death, and the occurrence of acute and chronic graft-versus-host disease (GVHD). Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest. The trial is conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **Busulfan**, a chemotherapeutic agent, as part of the conditioning regimen for allogeneic stem cell transplantation in patients with poor prognosis myeloid malignancies. **Busulfan** is provided as a 6 mg/ml concentrate for solution for infusion, manufactured by Accord Healthcare Limited. The pharmaceutical form is a **solution for infusion**, and it is administered via **intravenous infusion**. The dosing regimen includes a maximum daily dose of 3.2 mg/kg and a total maximum dose of 12.8 mg/kg over a treatment period of 4 days. Compliance with the dosing schedule is monitored through regular assessments of infusion rates and patient response.

**Thymoglobuline**, an immunosuppressive agent, is used as an auxiliary treatment in the trial. It is a rabbit anti-human thymocyte immunoglobulin provided as a 5 mg/ml powder for solution for infusion, produced by Sanofi B.V. The pharmaceutical form is a **solution for infusion**, administered via **IV infusion**. The dosing schedule includes a maximum daily dose of 2.5 mg/kg and a total maximum dose of 5 mg/kg over a treatment period of 2 days. The administration of **Thymoglobuline** is carefully monitored to ensure patient safety and adherence to the protocol.

**Fludarabine phosphate**, another chemotherapeutic agent, is included in the conditioning regimen. It is provided as a 25 mg/ml solution to be diluted for injection or infusion, manufactured by Accord Healthcare B.V. The pharmaceutical form is a **solution for injection/infusion**, administered via **IV infusion**. The dosing regimen consists of a maximum daily dose of 30 mg/m² and a total maximum dose of 150 mg/m² over a treatment period of 5 days. Patient compliance and response to **Fludarabine phosphate** are monitored through regular clinical evaluations and laboratory assessments.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to progression or death, which will provide a direct measure of the treatment's impact on disease progression and overall survival in patients with high-risk **myeloid malignancies**. Secondary endpoints include time to death and cause of death, time to acute and chronic graft-versus-host disease (GVHD) according to the NIH classification, and relapse rates. Additionally, response to treatment will be evaluated, along with hematological recovery, defined as achieving 500 absolute neutrophil count (ANC) and 50,000 platelets without transfusion. Full donor chimerism achievement will be assessed at months 1, 2, and 3 post-transplantation. The occurrence of grade 3-4 adverse events, as per the CTC AE v4.0 scale, will be monitored within six months following conditioning therapy.